]> hasSelector The relationship between a oa:SpecificResource and a oa:Selector. See http://www.w3.org/ns/oa#hasSelector Annotation Typically an Annotation has a single Body (oa:hasBody), which is the comment or other descriptive resource, and a single Target (oa:hasTarget) that the Body is somehow 'about'. The Body provides the information which is annotating the Target. See http://www.w3.org/ns/oa#Annotation TextQuoteSelector A Selector that describes a textual segment by means of quoting it, plus passages before or after it. See http://www.w3.org/ns/oa#TextQuoteSelector Mexiletine HCl,Watson Laboratories, Inc.;2008-04-29. setId: AB73778B-6794-441C-B127-610A6D0733EA. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=AB73778B-6794-441C-B127-610A6D0733EA. Last Accessed: 10/09/2015. SPORANOX,Janssen Pharmaceuticals, Inc.;2015-04-23. setId: a4d555fa-787c-40fb-bb7d-b0d4f7318fd0. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0. Last Accessed: 10/09/2015. SINGULAIR,A-S Medication Solutions LLC;2009-09-08. setId: a99f55de-39d1-483a-ba88-dbda5613c6a7. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a99f55de-39d1-483a-ba88-dbda5613c6a7. Last Accessed: 10/09/2015. Biaxin,AbbVie Inc.;2015-01-08. setId: aa44552c-3cfe-4111-8aa5-4251aeed9be9. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=aa44552c-3cfe-4111-8aa5-4251aeed9be9. Last Accessed: 10/09/2015. Nefazodone hydrochloride,Ranbaxy Pharmaceuticals Inc.;2008-12-24. setId: b1d149db-ad43-4f3f-aef1-fb0395ba4191. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b1d149db-ad43-4f3f-aef1-fb0395ba4191. Last Accessed: 10/09/2015. Alprazolam,Rebel Distributors Corp;2012-05-08. setId: b5e516a0-d0f4-4613-ab56-b1bb440fcb78. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b5e516a0-d0f4-4613-ab56-b1bb440fcb78. Last Accessed: 10/09/2015. ABILIFY,Otsuka America Pharmaceutical, Inc.;2014-07-03. setId: c040bd1d-45b7-49f2-93ea-aed7220b30ac. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c040bd1d-45b7-49f2-93ea-aed7220b30ac. Last Accessed: 10/09/2015. Ciprofloxacin,Apotex Corp;2013-10-09. setId: c103da18-a822-4944-1bd7-8ecdb5205d69. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c103da18-a822-4944-1bd7-8ecdb5205d69. Last Accessed: 10/09/2015. Bupropion hydrochloride,Actavis South Atlantic LLC;2011-12-27. setId: c2126e2d-3b46-40dd-8168-6d0368e5d233. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c2126e2d-3b46-40dd-8168-6d0368e5d233. Last Accessed: 10/09/2015. VFEND,Roerig;2015-04-14. setId: ce3ef5cf-3087-4d92-9d94-9eb8287228db. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ce3ef5cf-3087-4d92-9d94-9eb8287228db. Last Accessed: 10/09/2015. Fluconazole,Mylan Pharmaceuticals Inc.;2012-11-30. setId: cf26b007-df4f-4936-b2d3-183969761f69. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cf26b007-df4f-4936-b2d3-183969761f69. Last Accessed: 10/09/2015. Lovastatin,Rebel Distributors Corp;2011-12-13. setId: d3620ebe-87e1-4a93-96cc-ff20ddbb30b2. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d3620ebe-87e1-4a93-96cc-ff20ddbb30b2. Last Accessed: 10/09/2015. Zyprexa ,Eli Lilly and Company ;2014-12-19. setId: d5051fbc-846b-4946-82df-341fb1216341. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d5051fbc-846b-4946-82df-341fb1216341. Last Accessed: 10/09/2015. Edluar,Meda Pharmaceuticals;2009-03-27. setId: de965605-268a-4479-86f7-84de949cf36f. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=de965605-268a-4479-86f7-84de949cf36f. Last Accessed: 10/09/2015. CRIXIVAN,Merck Sharp & Dohme Corp.;2015-03-27. setId: e19405d9-d9a1-4072-5b9e-40cd3ae4bf1f. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e19405d9-d9a1-4072-5b9e-40cd3ae4bf1f. Last Accessed: 10/09/2015. AVANDIA,GlaxoSmithKline LLC;2014-05-07. setId: ec682aec-e98f-41a1-9d21-eb7580ea3a8a. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ec682aec-e98f-41a1-9d21-eb7580ea3a8a. Last Accessed: 10/09/2015. Lunesta,Sunovion Pharmaceuticals Inc.;2015-03-26. setId: fd047b2b-05a6-4d99-95cb-955f14bf329f. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd047b2b-05a6-4d99-95cb-955f14bf329f. Last Accessed: 10/09/2015. Pristiq ,Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.;2015-03-30. setId: 0f43610c-f290-46ea-d186-4f998ed99fce. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0f43610c-f290-46ea-d186-4f998ed99fce. Last Accessed: 10/09/2015. PAROXETINE,Apotex Corp.;2014-09-01. setId: 08320ea3-8f93-6f04-5d1c-f69af3eb5a81. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=08320ea3-8f93-6f04-5d1c-f69af3eb5a81. Last Accessed: 10/09/2015. Lexapro,Forest Laboratories, Inc.;2014-10-31. setId: 13bb8267-1cab-43e5-acae-55a4d957630a. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=13bb8267-1cab-43e5-acae-55a4d957630a. Last Accessed: 10/09/2015. REYATAZ,E.R. Squibb & Sons, L.L.C.;2015-03-27. setId: 165cff62-b284-4a27-a65d-9ec8a5bfcdd8. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=165cff62-b284-4a27-a65d-9ec8a5bfcdd8. Last Accessed: 10/09/2015. SAPHRIS,Organon Pharmaceuticals USA;2013-03-12. setId: 17209c32-56eb-4f84-954d-aed7b7a1b18d. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=17209c32-56eb-4f84-954d-aed7b7a1b18d. Last Accessed: 10/09/2015. Cymbalta,Eli Lilly and Company;2015-04-06. setId: 2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba. Last Accessed: 10/09/2015. Cymbalta,Eli Lilly and Company;2015-04-06. setId: 2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2f7d4d67-10c1-4bf4-a7f2-c185fbad64ba . Last Accessed: 10/09/2015. Strattera,Eli Lilly and Company ;2015-04-06. setId: 309de576-c318-404a-bc15-660c2b1876fb. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=309de576-c318-404a-bc15-660c2b1876fb. Last Accessed: 10/09/2015. REMERONSOLTAB,Organon USA Inc.;2015-04-17. setId: 31f48378-27db-424f-a4c5-82584a553c35. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=31f48378-27db-424f-a4c5-82584a553c35. Last Accessed: 10/09/2015. Fanapt,Vanda Pharmaceuticals Inc.;2011-03-21. setId: 33f60b40-3fca-11de-8f56-0002a5d5c51b. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=33f60b40-3fca-11de-8f56-0002a5d5c51b. Last Accessed: 10/09/2015. Tamoxifen Citrate,Teva Pharmaceuticals USA Inc;2012-06-29. setId: 407a372d-4448-4d53-afd4-eb0e74bbc336. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=407a372d-4448-4d53-afd4-eb0e74bbc336. Last Accessed: 10/09/2015. Celexa,Forest Laboratories, Inc.;2014-07-14. setId: 4259d9b1-de34-43a4-85a8-41dd214e9177. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4259d9b1-de34-43a4-85a8-41dd214e9177 . Last Accessed: 10/09/2015. Ketek,sanofi-aventis U.S. LLC;2015-03-25. setId: 4471223e-9023-457e-be2e-8e4e0c2d94d1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4471223e-9023-457e-be2e-8e4e0c2d94d1. Last Accessed: 10/09/2015. Sensipar,Amgen Inc;2014-11-25. setId: 45028573-13c4-4c8b-ae62-6c75bba97c81. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=45028573-13c4-4c8b-ae62-6c75bba97c81. Last Accessed: 10/09/2015. SEROQUEL,AstraZeneca Pharmaceuticals LP;2013-10-29. setId: 473a3ac4-67f4-4782-baa9-7f9bdd8761f4. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=473a3ac4-67f4-4782-baa9-7f9bdd8761f4. Last Accessed: 10/09/2015. AcipHex,Eisai Inc.;2014-12-30. setId: 5d103551-978f-472a-9c62-51e6e4dea068. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5d103551-978f-472a-9c62-51e6e4dea068. Last Accessed: 10/09/2015. Prozac ,Eli Lilly and Company;2015-02-04. setId: 5f356c1b-96bd-4ef1-960c-91cf4905e6b1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5f356c1b-96bd-4ef1-960c-91cf4905e6b1. Last Accessed: 10/09/2015. Nefazodone Hydrochloride,Teva Pharmaceuticals USA Inc;2014-06-02. setId: 51ff7db5-aaf9-4c3c-86e6-958ebf16b60f. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=51ff7db5-aaf9-4c3c-86e6-958ebf16b60f. Last Accessed: 10/09/2015. Fluvoxamine Maleate,Mylan Pharmaceuticals Inc.;2014-12-08. setId: 53664f8d-3a93-9f2b-daee-380707e4062c. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=53664f8d-3a93-9f2b-daee-380707e4062c. Last Accessed: 10/09/2015. ACCOLATE,AstraZeneca Pharmaceuticals LP;2013-11-15. setId: 5550433b-8c9c-4378-058f-6bb724c4f18c. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5550433b-8c9c-4378-058f-6bb724c4f18c. Last Accessed: 10/09/2015. Thioridazine Hydrochloride,Mylan Pharmaceuticals Inc.;2010-09-16. setId: 56b3f4c2-52af-4947-b225-6808ae9f26f5. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=56b3f4c2-52af-4947-b225-6808ae9f26f5. Last Accessed: 10/09/2015. INVEGA,Janssen Pharmaceuticals, Inc.;2014-05-02. setId: 7b8e5b26-b9e4-4704-921b-3c3c0d159916. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7b8e5b26-b9e4-4704-921b-3c3c0d159916. Last Accessed: 10/09/2015. Lamisil,Novartis Pharmaceuticals Corporation;2015-02-02. setId: 7c6c1494-fb92-4442-bcff-764b77397495. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7c6c1494-fb92-4442-bcff-764b77397495. Last Accessed: 10/09/2015. Prevacid,Takeda Pharmaceuticals America, Inc.;2015-01-22. setId: 71ba78cb-7e46-43eb-9425-fa130f537f84. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=71ba78cb-7e46-43eb-9425-fa130f537f84. Last Accessed: 10/09/2015. Zaleplon,Teva Pharmaceuticals USA Inc;2013-08-06. setId: 71be4cb7-a42f-43be-9b9b-f090edb2fd21. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=71be4cb7-a42f-43be-9b9b-f090edb2fd21. Last Accessed: 10/09/2015. Pantoprazole Sodium ,Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.;2015-01-21. setId: 742ca9f4-9fba-44d4-29a8-1fe3a04f1af6. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=742ca9f4-9fba-44d4-29a8-1fe3a04f1af6. Last Accessed: 10/09/2015. Atorvastatin Calcium,Mylan Pharmaceuticals Inc.;2012-03-01. setId: 8a201c80-a51d-4c1c-963b-488c071908c0. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8a201c80-a51d-4c1c-963b-488c071908c0. Last Accessed: 10/09/2015. Ketoconazole,Taro Pharmaceuticals U.S.A., Inc.;2014-04-15. setId: 8ca815a8-bccb-4ee2-a042-922373329cae. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8ca815a8-bccb-4ee2-a042-922373329cae. Last Accessed: 10/09/2015. CELEBREX,G.D. Searle LLC Division of Pfizer Inc;2014-12-02. setId: 8d52185d-421f-4e34-8db7-f7676db2a226. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8d52185d-421f-4e34-8db7-f7676db2a226. Last Accessed: 10/09/2015. Geodon,Roerig;2014-12-15. setId: 8326928a-2cb6-4f7f-9712-03a425a14c37. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8326928a-2cb6-4f7f-9712-03a425a14c37. Last Accessed: 10/09/2015. Clozapine,Mylan Pharmaceuticals Inc.;2015-02-20. setId: 883b5d43-0339-7dc1-f775-93791fb9b978. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=883b5d43-0339-7dc1-f775-93791fb9b978. Last Accessed: 10/09/2015. Paroxetine,Mylan Pharmaceuticals Inc.;2014-10-17. setId: 89dd7e24-85fc-4152-89ea-47ec2b48a1ed. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=89dd7e24-85fc-4152-89ea-47ec2b48a1ed. Last Accessed: 10/09/2015. Amiodarone Hydrochloride,ALPHAPHARM PTY LTD;2006-09-12. setId: 99991CC3-7271-44FC-91C3-3CAB0BBE7645. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=99991CC3-7271-44FC-91C3-3CAB0BBE7645. Last Accessed: 10/09/2015. diltiazem_increases_auc_triazolam paroxetine_increases_auc_risperidone desvenlafaxine_substrate_of_cyp2d6 atorvastatin_substrate_of_cyp3a5 atorvastatin_substrate_of_cyp3a4 fluvastatin_substrate_of_cyp2c8 fluvastatin_substrate_of_cyp2c9 aripiprazole_substrate_of_cyp1a2 aripiprazole_substrate_of_cyp1a1 atorvastatin_substrate_of_cyp2b6 ziprasidone_substrate_of_cyp1a2 atorvastatin_substrate_of_cyp2c19 clarithromycin_increases_auc_midazolam alprazolam_substrate_of_cyp3a4 alprazolam_substrate_of_cyp3a5 duloxetine_substrate_of_cyp2d6 nefazodone_substrate_of_cyp3a4 R-citalopram_substrate_of_cyp2c19 modafinil_substrate_of_cyp3a4 lovastatin_substrate_of_cyp3a4 quetiapine_substrate_of_cyp1a2 eszopiclone_substrate_of_cyp3a4 escitalopram_substrate_of_cyp3a4 itraconazole_increases_auc_midazolam bupropion_substrate_of_cyp2b6 cinacalcet_substrate_of_cyp1a2 aripiprazole_substrate_of_cyp2c8 celecoxib_substrate_of_cyp2c9 pantoprazole_substrate_of_cyp2c19 clozapine_substrate_of_cyp2d6 alprazolam_substrate_of_cyp1a2 aripiprazole_substrate_of_cyp2e1 perphenazine_substrate_of_cyp1a2 voriconazole_substrate_of_cyp3a4 itraconazole_increases_auc_lovastatin asenapine_substrate_of_cyp2d6 mirtazapine_substrate_of_cyp1a2 quetiapine_substrate_of_cyp2c9 clozapine_substrate_of_cyp3a4 aripiprazole_substrate_of_cyp2a6 voriconazole_substrate_of_cyp2c19 escitalopram_substrate_of_cyp2d6 atorvastatin_substrate_of_cyp2e1 ziprasidone_substrate_of_cyp2c9 nefazodone_substrate_of_cyp2c19 fluoxetine_increases_auc_alprazolam escitalopram_substrate_of_cyp2c19 rabeprazole_substrate_of_cyp3a4 risperidone_substrate_of_cyp2d6 aripiprazole_substrate_of_cyp2b6 sertraline_substrate_of_cyp2c19 nefazodone_substrate_of_cyp2c8 iloperidone_substrate_of_cyp2d6 pantoprazole_substrate_of_cyp3a4 venlafaxine_substrate_of_cyp2d6 voriconazole_substrate_of_cyp2c9 venlafaxine_increases_auc_risperidone aripiprazole_substrate_of_cyp3a4 clarithromycin_substrate_of_cyp3a4 perphenazine_substrate_of_cyp2d6 tamoxifen_substrate_of_cyp2d6 mirtazapine_substrate_of_cyp2b6 zolpidem_substrate_of_cyp3a5 zolpidem_substrate_of_cyp3a4 aripiprazole_substrate_of_cyp2c19 atorvastatin_substrate_of_cyp2d6 aripiprazole_substrate_of_cyp2d6 itraconazole_increases_auc_atorvastatin zafirlukast_substrate_of_cyp2c9 atorvastatin_substrate_of_cyp1a1 iloperidone_substrate_of_cyp2a6 trazodone_substrate_of_cyp3a4 quetiapine_substrate_of_cyp2e1 risperidone_substrate_of_cyp3a4 haloperidol_substrate_of_cyp3a4 duloxetine_substrate_of_cyp1a2 fluvastatin_substrate_of_cyp3a4 zaleplon_substrate_of_cyp3a4 cimetidine_increases_auc_citalopram zaleplon_substrate_of_cyp2d6 eszopiclone_substrate_of_cyp2e1 iloperidone_substrate_of_cyp3a4 perphenazine_substrate_of_cyp2c19 mirtazapine_substrate_of_cyp2c19 fluvoxamine_substrate_of_cyp2d6 rosuvastatin_substrate_of_cyp3a4 tamoxifen_substrate_of_cyp3a5 fluoxetine_substrate_of_cyp2d6 midazolam_substrate_of_cyp3a5 nefazodone_increases_auc_triazolam lansoprazole_substrate_of_cyp2c19 cinacalcet_substrate_of_cyp3a4 quetiapine_substrate_of_cyp2c19 iloperidone_substrate_of_cyp1a2 R-citalopram_substrate_of_cyp3a4 iloperidone_substrate_of_cyp1a1 iloperidone_substrate_of_cyp2c9 iloperidone_substrate_of_cyp2c8 lansoprazole_substrate_of_cyp3a5 thioridazine_substrate_of_cyp2d6 cimetidine_increases_auc_escitalopram clozapine_substrate_of_cyp1a2 nefazodone_substrate_of_cyp2c9 nefazodone_substrate_of_cyp1a2 tamoxifen_substrate_of_cyp3a4 citalopram_substrate_of_cyp2c19 atorvastatin_substrate_of_cyp2c9 iloperidone_substrate_of_cyp2c19 clarithromycin_substrate_of_cyp2d6 mirtazapine_substrate_of_cyp2a6 paroxetine_substrate_of_cyp2d6 ketoconazole_increases_auc_simvastatin cimetidine_increases_auc_theophylline cinacalcet_substrate_of_cyp2d6 mirtazapine_substrate_of_cyp2e1 mirtazapine_substrate_of_cyp3a4 mirtazapine_substrate_of_cyp3a5 ziprasidone_substrate_of_cyp3a4 olanzapine_substrate_of_cyp2d6 clarithromycin_substrate_of_cyp1a2 citalopram_substrate_of_cyp3a4 quetiapine_substrate_of_cyp3a4 rabeprazole_substrate_of_cyp3a5 fluconazole_increases_auc_midazolam diltiazem_substrate_of_cyp3a5 diltiazem_substrate_of_cyp3a4 mirtazapine_substrate_of_cyp2d6 iloperidone_substrate_of_cyp2e1 tamoxifen_substrate_of_cyp2c9 citalopram_substrate_of_cyp2d6 ranolazine_substrate_of_cyp2d6 aripiprazole_substrate_of_cyp2c9 perphenazine_substrate_of_cyp3a4 lansoprazole_substrate_of_cyp3a4 duloxetine_increases_auc_theophylline venlafaxine_substrate_of_cyp3a4 rabeprazole_substrate_of_cyp2c19 ziprasidone_substrate_of_cyp2d6 iloperidone_substrate_of_cyp2b6 eszopiclone_inhibits_CYP2E1 nefazodone_inhibits_cyp1a2 topiramate_inhibits_cyp2b6 mirtazapine_inhibits_cyp2c9 topiramate_inhibits_cyp2e1 fluconazole_inhibits_cyp2c9 omeprazole_increases_auc_escitalopram quetiapine_inhibits_cyp3a4 zafirlukast_inhibits_cyp3a4 ritonavir_inhibits_cyp3a5 ritonavir_inhibits_cyp3a4 R-citalopram_inhibits_cyp2e1 aripiprazole_inhibits_cyp2d6 rosiglitazone_inhibits_cyp1a2 rosiglitazone_inhibits_cyp1a1 duloxetine_inhibits_cyp2c19 paliperidone_inhibits_cyp3a4 venlafaxine_increases_auc_haloperidol verapamil_inhibits_cyp3a4 verapamil_inhibits_cyp3a5 atazanavir_inhibits_cyp2a6 erythromycin_inhibits_cyp3a4 montelukast_inhibits_cyp2c19 omeprazole_inhibits_cyp2d6 cinacalcet_inhibits_cyp2c19 escitalopram_inhibits_cyp2c19 eszopiclone_inhibits_CYP2A6 ziprasidone_inhibits_cyp1a2 ketoconazole_increases_auc_zolpidem citalopram_inhibits_cyp2c9 fluoxetine_inhibits_cyp2d6 celecoxib_inhibits_cyp3a4 paliperidone_inhibits_cyp1a2 duloxetine_inhibits_cyp3a5 duloxetine_inhibits_cyp3a4 fluconazole_inhibits_cyp3a4 zafirlukast_inhibits_cyp2c9 fluvoxamine_inhibits_cyp2c19 paliperidone_inhibits_cyp2c9 fluoxetine_increases_auc_propafenone paliperidone_inhibits_cyp2c8 atazanavir_inhibits_cyp3a5 atazanavir_inhibits_cyp3a4 risperidone_inhibits_cyp2c19 perphenazine_inhibits_cyp2c19 eszopiclone_inhibits_CYP3A4 atazanavir_inhibits_cyp2e1 cinacalcet_inhibits_cyp3a5 cinacalcet_inhibits_cyp3a4 R-citalopram_inhibits_cyp1a2 erythromycin_increases_auc_triazolam modafinil_inhibits_cyp2c19 iloperidone_inhibits_cyp2d6 venlafaxine_inhibits_cyp2c9 ciprofloxacin_inhibits_cyp1a2 propafenone_inhibits_cyp1a2 ritonavir_inhibits_cyp2d6 citalopram_inhibits_cyp1a2 celecoxib_inhibits_cyp2c9 escitalopram_inhibits_cyp2c9 eszopiclone_inhibits_CYP2D6 fluconazole_increases_auc_fluvastatin topiramate_inhibits_cyp2c9 citalopram_inhibits_cyp2d6 ranolazine_inhibits_cyp2d6 diltiazem_inhibits_cyp3a4 celecoxib_inhibits_cyp2d6 citalopram_inhibits_cyp2c19 R-citalopram_inhibits_cyp2d6 montelukast_inhibits_cyp3a4 clozapine_inhibits_cyp2c19 amiodarone_inhibits_cyp2c9 paroxetine_increases_auc_mirtazapine amiodarone_inhibits_cyp2d6 celecoxib_inhibits_cyp2c19 paliperidone_inhibits_cyp2d6 sertraline_inhibits_cyp2d6 lansoprazole_inhibits_cyp2d6 paliperidone_inhibits_cyp2c19 voriconazole_inhibits_cyp2c9 venlafaxine_inhibits_cyp1a2 rosiglitazone_inhibits_cyp2c19 indinavir_inhibits_cyp3a5 clarithromycin_increases_auc_triazolam cimetidine_increases_auc_ziprasidone indinavir_inhibits_cyp3a4 ziprasidone_inhibits_cyp2c9 aripiprazole_inhibits_cyp1a2 atazanavir_inhibits_cyp2c19 topiramate_inhibits_cyp1a2 quetiapine_inhibits_cyp2c9 norfloxacin_inhibits_cyp1a2 trimethoprim_inhibits_cyp2c8 topiramate_inhibits_cyp2d6 paliperidone_inhibits_cyp3a5 fluvoxamine_increases_auc_lansoprazole citalopram_inhibits_cyp2e1 aripiprazole_inhibits_cyp2c19 mirtazapine_inhibits_cyp2d6 rosiglitazone_inhibits_cyp3a5 quetiapine_inhibits_cyp1a2 haloperidol_inhibits_cyp2c19 voriconazole_inhibits_cyp3a4 atazanavir_inhibits_cyp2d6 duloxetine_inhibits_cyp2c9 rosiglitazone_inhibits_cyp2a6 clopidogrel_increases_auc_bupropion atomoxetine_inhibits_cyp1a2 ketoconazole_inhibits_cyp3a4 fluconazole_inhibits_cyp3a5 quetiapine_inhibits_cyp2d6 ziprasidone_inhibits_cyp2d6 verapamil_inhibits_cyp1a2 amiodarone_inhibits_cyp3a4 indinavir_inhibits_cyp2b6 indinavir_inhibits_cyp2e1 clarithromycin_inhibits_cyp3a4 ketoconazole_increases_auc_venlafaxine clarithromycin_inhibits_cyp3a5 paliperidone_inhibits_cyp2a6 montelukast_inhibits_cyp2d6 montelukast_inhibits_cyp2a6 duloxetine_inhibits_cyp2d6 paliperidone_inhibits_cyp2e1 ziprasidone_inhibits_cyp2c19 atazanavir_inhibits_cyp2c9 ziprasidone_inhibits_cyp3a4 cinacalcet_inhibits_cyp1a2 fluoxetine_increases_auc_desipramine rosiglitazone_inhibits_cyp2b6 citalopram_inhibits_cyp3a4 escitalopram_inhibits_cyp2d6 topiramate_inhibits_cyp2c19 rosiglitazone_inhibits_cyp3a4 rosiglitazone_inhibits_cyp2c8 fluphenazine_inhibits_cyp2c19 bupropion_inhibits_cyp2d6 eszopiclone_inhibits_CYP2C9 R-citalopram_inhibits_cyp2c19 ketoconazole_increases_auc_triazolam gemfibrozil_inhibits_cyp2c8 cinacalcet_inhibits_cyp2c9 mirtazapine_inhibits_cyp2e1 aripiprazole_inhibits_cyp3a4 fluvoxamine_inhibits_cyp2c9 rosiglitazone_inhibits_cyp2e1 pantoprazole_inhibits_cyp2d6 thiothixene_inhibits_cyp2c19 escitalopram_inhibits_cyp1a2 nefazodone_inhibits_cyp3a5 paroxetine_increases_auc_paliperidone venlafaxine_inhibits_cyp3a4 quetiapine_inhibits_cyp2c19 R-citalopram_inhibits_cyp3a4 pravastatin_inhibits_cyp2c8 R-citalopram_inhibits_cyp2c9 rosiglitazone_inhibits_cyp2d6 telithromycin_inhibits_cyp3a4 atorvastatin_inhibits_cyp3a4 montelukast_inhibits_cyp2c8 quinidine_inhibits_cyp2d6 nefazodone_increases_auc_midazolam mirtazapine_inhibits_cyp2c19 topiramate_inhibits_cyp3a4 topiramate_inhibits_cyp3a5 eszopiclone_inhibits_CYP1A2 fluvoxamine_inhibits_cyp1a2 rosuvastatin_inhibits_cyp2c8 cinacalcet_inhibits_cyp2d6 cimetidine_inhibits_cyp1a2 atomoxetine_inhibits_cyp2d6 indinavir_inhibits_cyp2c9 cimetidine_increases_auc_quetiapine venlafaxine_inhibits_cyp2d6 atomoxetine_inhibits_cyp2c9 cimetidine_inhibits_cyp3a5 cimetidine_inhibits_cyp3a4 atazanavir_inhibits_cyp1a2 lansoprazole_inhibits_cyp3a4 topiramate_inhibits_cyp2a6 montelukast_inhibits_cyp2c9 eszopiclone_inhibits_CYP2C19 voriconazole_inhibits_cyp2c19 diltiazem_increases_auc_simvastatin aripiprazole_inhibits_cyp2c9 telithromycin_inhibits_cyp3a5 ranolazine_inhibits_cyp3a5 ranolazine_inhibits_cyp3a4 mexiletine_inhibits_cyp1a2 itraconazole_inhibits_cyp3a4 atazanavir_inhibits_cyp2b6 escitalopram_inhibits_cyp3a4 omeprazole_inhibits_cyp2c19 nefazodone_inhibits_cyp3a4 ketoconazole_increases_auc_midazolam cimetidine_increases_auc_mirtazapine rosiglitazone_inhibits_cyp2c9 terbinafine_inhibits_cyp2d6 montelukast_inhibits_cyp1a2 escitalopram_inhibits_cyp2e1 paroxetine_inhibits_cyp2d6 mirtazapine_inhibits_cyp1a2 chlorpromazine_inhibits_cyp2c19 indinavir_inhibits_cyp1a2 thioridazine_inhibits_cyp2c19 amiodarone_inhibits_cyp1a2 fluvoxamine_increases_auc_duloxetine simvastatin_inhibits_cyp3a4 terbinafine_increases_auc_venlafaxine terbinafine_increases_auc_paroxetine sertraline_increases_auc_desipramine fluvoxamine_increases_auc_mexiletine fluvoxamine_increases_auc_omeprazole erythromycin_increases_auc_midazolam erythromycin_increases_auc_atorvastatin clarithromycin_increases_auc_lansoprazole fluvoxamine_increases_auc_tolbutamide fluvoxamine_increases_auc_clozapine fluvoxamine_increases_auc_thioridazine clarithromycin_increases_auc_trazodone itraconazole_increases_auc_rosuvastatin itraconazole_increases_auc_alprazolam clarithromycin_increases_auc_pravastatin cimetidine_increases_auc_venlafaxine aripiprazole_increases_auc_escitalopram fluvoxamine_increases_auc_quinidine ketoconazole_increases_auc_alprazolam ketoconazole_increases_auc_desvenlafaxine itraconazole_increases_auc_pravastatin erythromycin_increases_auc_alprazolam erythromycin_increases_auc_simvastatin fluoxetine_increases_auc_olanzapine itraconazole_increases_auc_triazolam fluvoxamine_increases_auc_theophylline paroxetine_increases_auc_desipramine diphenhydramine_increases_auc_venlafaxine erythromycin_increases_auc_quetiapine aripiprazole_increases_auc_venlafaxine clarithromycin_increases_auc_atorvastatin diltiazem_increases_auc_midazolam itraconazole_increases_auc_zolpidem verapamil_increases_auc_risperidone prasugrel_increases_auc_bupropion ticlopidine_increases_auc_bupropion paroxetine_increases_auc_duloxetine ritonavir_increases_auc_trazodone cimetidine_increases_auc_paroxetine ketoconazole_increases_auc_amitriptyline cimetidine_increases_auc_amitriptyline nefazodone_increases_auc_alprazolam cimetidine_increases_auc_doxepin cimetidine_increases_auc_imipramine fluoxetine_increases_auc_imipramine ketoconazole_increases_auc_imipramine paroxetine_increases_auc_imipramine verapamil_increases_auc_imipramine diltiazem_increases_auc_imipramine paroxetine_increases_auc_nortriptyline cimetidine_increases_auc_sertraline desvenlafaxine_increases_auc_desipramine fluconazole_increases_auc_triazolam citalopram_increases_auc_desipramine venlafaxine_increases_auc_imipramine venlafaxine_increases_auc_desipramine quinidine_increases_auc_venlafaxine bupropion_increases_auc_desipramine R-citalopram_substrate_of_cyp2d6 ziprasidone_substrate_of_cyp2c19 clarithromycin_substrate_of_cyp2c9 simvastatin_substrate_of_cyp3a4 nefazodone_substrate_of_cyp2d6 2.835 2.46 8.45 7 10.8 14.8 1.318 1.32 2.5 3.899 1.72 12.55 1.458 3.55 3.726 1.13 1.51 1.83 1.5 2.06 1.837 1.17 5.255 1.069 9.03 3.82 1.6 4.8 7.43 22.4 9.16 1.16 4.56 15.9 1.24 4.817 1.54 4.6 6 4.9 3.03 1.2 1.37 1.54 1.5 1.55 1.74 4.417 1.325 1.71 2.84 1.99 1.28 1.615 2.1 1.819 1.62 1.07 1.42 1.76 3.983 1.486 1.61 6.3 1.18 27 5.381 3.87 3.33 5.2 4.28 4.64 2.42 2.29 1.183 3.75 1.34 1.987 1.82 1 1.117 0 1.32 1.47 2007-07-02T17:38:07 2007-11-13T08:46:01 2007-09-25T08:35:33 2007-09-25T07:52:24 2007-09-25T08:33:11 2007-09-27T10:18:37 2007-10-20T09:40:46 2007-10-20T09:37:05 2009-06-19T17:46:18 2007-06-26T07:11:48 2007-06-26T07:39:29 2007-07-02T10:51:34 2007-11-13T08:58:59 2007-06-26T06:27:38 2007-06-26T07:14:26 2009-05-05T17:43:52 2009-06-20T13:36:32 2010-02-13T09:12:03 2009-06-12T19:19:09 2009-09-24T12:45:45 2007-09-28T14:01:54 2007-10-29T13:18:39 2009-09-23T15:48:01 2007-10-30T06:43:43 2009-09-23T16:09:10 2009-06-12T19:11:52 2009-06-20T15:22:12 2009-09-24T00:00:00 2009-09-24T10:57:14 2009-09-24T13:17:14 2009-05-15T11:01:27 2009-06-20T14:35:57 2009-06-15T14:26:44 2009-06-15T16:29:22 2009-06-16T16:47:59 2009-09-24T00:00:00 2009-06-15T15:23:39 2010-02-13T07:59:40 2009-05-15T11:02:18 2010-02-12T18:20:56 2009-09-24T00:00:00 2009-06-12T19:07:47 2009-05-15T10:09:13 2009-06-12T19:03:08 2009-09-24T13:56:23 2007-10-30T07:09:46 2009-09-24T13:58:07 2009-06-17T13:29:24 2010-02-13T09:39:40 2009-09-28T11:38:05 2010-01-11T18:29:32 2010-01-11T18:32:05 2009-09-24T13:18:40 2009-05-15T10:28:04 2009-06-20T14:01:46 2009-06-20T14:04:45 2007-10-30T07:28:31 2009-09-24T00:00:00 2009-04-29T19:50:52 2009-05-06T14:19:26 2007-10-20T08:21:46 2007-10-20T08:39:39 2009-06-15T14:27:57 2009-06-15T16:31:59 2009-06-16T18:11:05 2009-06-20T12:43:54 2009-09-28T12:08:09 2007-06-05T14:37:35 2009-09-24T00:00:00 2009-11-09T12:48:23 2009-11-09T12:45:49 2009-11-09T12:51:14 2009-04-29T19:51:34 2009-09-24T15:17:23 2009-05-14T14:33:26 2010-02-13T09:43:11 2009-06-17T07:57:02 2009-05-05T17:51:26 2007-10-29T12:20:41 2007-10-20T09:39:51 2009-11-09T12:41:35 2010-01-11T18:27:15 2009-06-15T16:30:47 2009-05-15T08:46:10 2009-06-16T18:52:14 2009-09-24T00:00:00 2009-05-14T14:29:52 2009-06-22T15:33:44 2007-07-02T11:06:38 2010-09-22T15:33:48 2009-09-24T10:17:24 2009-09-24T00:00:00 2009-09-24T10:51:26 2009-06-12T19:22:19 2009-09-24T10:16:14 2009-04-29T20:08:03 2009-06-15T15:36:15 2009-05-15T11:00:35 2010-02-12T18:15:23 2009-09-24T00:00:00 2010-09-16T15:08:01 2009-05-15T10:38:46 2009-06-16T16:42:46 2009-09-24T00:00:00 2009-06-15T15:24:41 2010-02-13T07:52:43 2009-06-15T15:25:44 2009-05-15T11:20:22 2009-06-19T12:45:00 2009-06-19T17:43:12 2009-06-20T13:13:40 2007-10-30T11:25:31 2007-09-24T10:14:08 2009-06-16T16:55:20 2010-02-12T18:32:55 2009-05-15T09:50:28 2009-06-16T17:22:10 2010-02-13T09:22:55 2009-09-24T13:59:22 2007-05-29T09:02:40 2007-05-29T08:49:06 2009-06-15T15:22:05 2010-02-13T07:56:10 2012-02-09T10:26:38 2009-09-24T00:00:00 2009-09-24T15:49:33 2009-06-15T14:25:13 2009-06-15T16:27:12 2009-09-24T10:14:47 2009-06-20T14:13:20 2009-09-24T13:53:17 2009-06-19T12:33:21 2007-10-20T08:13:36 2010-02-12T00:00:00 2007-10-16T11:03:11 2010-02-12T13:56:37 2009-09-22T18:18:19 2009-04-29T19:44:42 2009-04-29T19:44:07 2007-09-25T08:58:04 2009-05-14T13:40:01 2009-06-19T12:30:38 2007-09-25T08:59:05 2010-02-12T00:00:00 2009-04-29T19:46:49 2007-10-29T11:25:10 2007-08-14T06:08:03 2009-04-29T19:49:12 2010-01-11T19:02:26 2010-02-12T00:00:00 2009-04-29T19:45:20 2007-09-25T09:01:13 2009-06-19T12:32:07 2010-02-12T00:00:00 2009-04-29T19:46:08 2010-02-12T00:00:00 2010-09-15T13:20:38 2010-02-12T00:00:00 2009-04-29T19:48:02 2007-09-25T09:00:02 2007-09-25T08:56:58 2010-01-11T00:00:00 2010-02-12T00:00:00 2009-11-09T12:39:21 2010-02-12T00:00:00 2007-09-28T12:06:44 2010-02-12T00:00:00 2010-09-16T13:53:17 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-02-12T00:00:00 2010-02-12T00:00:00 2007-09-25T09:02:14 2010-01-11T00:00:00 2007-10-20T08:16:32 2010-02-12T00:00:00 2007-10-22T12:38:50 2010-02-12T00:00:00 2007-10-20T08:15:16 2009-06-12T13:16:14 2010-01-11T00:00:00 2009-04-29T19:48:35 2009-06-19T12:41:48 2010-01-11T00:00:00 2007-09-27T11:44:51 2009-06-30T13:32:26 2009-09-24T00:00:00 2007-11-13T08:06:22 2009-06-30T14:07:18 2009-06-30T14:06:14 2010-01-11T17:43:46 2010-01-11T17:52:19 2009-06-30T14:26:54 2009-06-30T14:28:00 2007-06-25T13:47:05 2007-10-16T09:38:08 2009-05-05T17:04:02 2009-05-15T11:16:23 2007-12-10T15:09:10 2009-06-16T17:07:34 2007-10-22T13:08:14 2007-12-10T15:42:25 2009-06-30T13:33:58 2009-09-24T00:00:00 2009-09-24T15:41:53 2009-05-05T17:27:55 2009-05-15T08:52:34 2009-06-30T12:48:44 2010-01-11T15:40:48 2010-08-23T14:30:03 2009-06-30T12:47:19 2010-01-11T15:38:56 2009-09-24T12:37:09 2010-01-11T18:24:21 2009-06-30T12:58:54 2010-01-11T16:43:17 2009-06-30T14:03:13 2010-01-11T17:46:31 2010-01-11T17:54:47 2009-09-25T00:00:00 2007-06-05T13:57:26 2010-09-15T13:07:44 2007-05-29T11:43:17 2009-09-24T10:54:45 2009-09-25T09:49:39 2009-06-30T12:43:42 2010-01-11T16:39:16 2009-06-30T12:45:54 2010-01-11T16:40:43 2009-04-29T20:01:03 2009-05-05T17:06:30 2009-05-15T10:42:02 2009-05-15T10:17:11 2009-09-24T00:00:00 2009-06-30T13:40:40 2009-06-30T13:39:31 2010-01-11T16:31:55 2010-01-11T16:59:43 2009-06-30T13:53:44 2009-06-30T15:15:52 2009-09-24T00:00:00 2007-05-21T15:16:35 2007-05-21T15:27:20 2010-08-10T14:42:58 2007-05-21T16:08:37 2010-01-11T17:05:33 2009-06-30T13:35:23 2009-06-30T14:29:36 2010-01-11T16:35:31 2007-06-05T14:12:44 2009-06-30T13:05:51 2010-01-11T16:45:51 2009-06-30T13:07:14 2010-01-11T16:47:28 2010-09-16T11:48:22 2009-04-29T20:02:14 2009-05-05T17:52:52 2009-06-20T13:44:41 2009-05-15T10:11:58 2009-05-15T10:51:26 2009-06-20T14:58:06 2009-06-30T13:37:42 2009-05-15T09:08:19 2009-06-30T13:52:12 2009-06-30T14:14:05 2007-10-29T13:08:09 2010-01-11T15:43:44 2010-01-11T15:46:06 2007-09-24T10:42:50 2010-01-11T17:38:30 2009-05-05T17:26:22 2009-05-15T09:03:48 2009-06-20T11:54:59 2009-09-24T12:22:35 2009-09-25T10:03:28 2009-09-25T10:47:42 2007-10-29T11:59:09 2009-06-30T12:57:08 2009-05-15T10:30:24 2009-06-30T12:55:42 2009-06-30T12:54:27 2009-09-24T00:00:00 2009-06-30T14:15:06 2009-09-25T00:00:00 2009-09-25T00:00:00 2009-06-30T13:42:29 2010-01-11T17:09:51 2010-08-23T15:39:12 2010-01-11T17:15:31 2010-01-11T17:03:24 2009-06-30T13:55:41 2009-06-30T13:51:06 2010-01-11T17:20:39 2010-01-11T17:23:29 2009-06-30T14:16:34 2010-01-11T17:40:55 2009-05-05T17:09:29 2009-06-16T17:10:18 2009-09-22T18:37:28 2009-06-16T17:12:46 2009-06-16T18:00:03 2010-01-11T17:35:08 2010-01-11T16:37:52 2009-11-09T00:00:00 2010-01-11T19:09:34 2009-09-21T00:00:00 2010-02-12T17:32:18 2009-09-21T00:00:00 2009-09-22T18:00:34 2010-08-10T14:29:24 2009-05-14T00:00:00 2009-04-29T19:38:21 2010-01-11T00:00:00 2010-01-11T00:00:00 2009-05-05T17:40:26 2009-06-10T00:00:00 2010-01-11T00:00:00 2010-01-11T00:00:00 2009-09-23T11:38:21 2009-09-21T00:00:00 2010-08-10T14:43:34 2009-05-14T00:00:00 2009-06-11T16:10:21 2009-11-09T00:00:00 2009-05-14T00:00:00 2009-06-19T17:06:15 2009-05-14T00:00:00 2010-02-12T14:53:49 2009-09-21T00:00:00 2009-06-10T00:00:00 2009-06-10T00:00:00 2007-06-05T07:52:40 2010-09-15T14:16:12 2009-05-05T17:39:38 2009-05-05T17:38:52 2009-06-10T00:00:00 2009-06-10T00:00:00 2009-06-10T00:00:00 2009-04-25T09:58:43 2009-04-25T10:18:23 2009-11-09T00:00:00 2010-01-11T00:00:00 2009-09-21T15:22:09 2012-02-16T21:49:26 2009-09-21T15:20:18 2009-09-21T00:00:00 2009-06-11T14:58:44 2009-05-14T13:49:46 2010-02-12T14:23:14 2009-09-21T00:00:00 2009-05-14T00:00:00 2009-06-11T15:15:34 2009-11-09T00:00:00 2009-09-21T00:00:00 2009-05-05T15:27:35 2009-09-22T17:58:27 2009-06-11T16:25:20 2010-01-11T00:00:00 2009-04-25T10:22:07 2009-09-21T00:00:00 2009-06-10T00:00:00 2009-09-23T11:41:27 2009-06-10T00:00:00 2009-05-14T13:48:13 2010-02-12T14:12:02 2012-05-09T12:02:07 2010-02-12T14:37:56 2010-01-11T00:00:00 2009-05-14T00:00:00 2009-06-19T17:08:33 2009-04-29T19:41:31 2010-01-11T00:00:00 2009-09-21T00:00:00 2009-09-22T17:50:11 2009-05-14T00:00:00 2009-09-21T00:00:00 2007-06-05T07:36:33 2009-06-10T00:00:00 2009-05-14T00:00:00 2009-04-29T19:39:57 2010-02-12T17:39:55 2010-01-11T00:00:00 2009-05-14T00:00:00 2009-04-25T10:21:12 2010-01-11T00:00:00 2009-05-05T17:37:51 2010-01-11T00:00:00 2007-06-05T07:46:02 2009-09-21T14:55:32 2009-05-14T00:00:00 2009-05-14T00:00:00 2009-05-14T13:42:42 2010-01-11T00:00:00 2010-01-11T00:00:00 2009-06-10T00:00:00 2009-06-10T00:00:00 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-09-22T12:19:19 2009-06-10T00:00:00 2009-05-14T00:00:00 2009-06-19T17:10:35 2010-01-11T00:00:00 2009-05-14T00:00:00 2009-09-21T00:00:00 2010-01-11T00:00:00 2009-05-14T00:00:00 2009-06-11T16:32:24 2010-02-12T14:46:20 2007-11-13T08:18:22 2009-05-14T13:37:41 2009-06-11T16:23:37 2009-09-21T00:00:00 2010-01-11T00:00:00 2010-01-11T00:00:00 2009-04-25T10:16:03 2009-11-09T00:00:00 2009-06-11T16:08:54 2009-09-21T00:00:00 2010-02-12T17:54:38 2010-09-16T12:29:46 2009-04-29T19:40:38 2010-01-11T00:00:00 2009-09-23T11:43:26 2009-04-25T10:20:16 2009-06-11T15:00:17 2009-05-14T13:07:10 2010-02-12T14:20:00 2009-05-14T00:00:00 2007-10-29T10:11:10 2009-06-11T15:12:49 2007-05-29T10:27:50 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-02-12T17:35:55 2009-09-21T00:00:00 2009-09-22T18:02:20 2009-09-21T00:00:00 2009-11-09T00:00:00 2007-10-29T10:23:54 2009-09-21T14:57:14 2009-09-21T15:02:28 2010-09-22T12:59:40 2010-09-16T12:05:16 2010-01-11T00:00:00 2009-09-21T14:59:07 2010-01-11T00:00:00 2009-09-23T11:47:32 2009-09-21T00:00:00 2009-09-22T17:55:50 2010-01-11T00:00:00 2010-01-11T19:14:00 2009-11-09T00:00:00 2009-04-29T19:39:11 2010-09-01T15:15:26 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-01-11T00:00:00 2010-01-11T19:12:06 2009-05-14T00:00:00 2010-02-12T15:01:51 2009-04-25T10:23:23 2010-01-11T00:00:00 2009-04-25T10:13:19 2007-11-13T13:26:37 2012-04-26T12:12:24 2010-09-01T15:40:49 2010-09-15T15:26:19 2009-05-05T15:37:50 2009-05-05T16:11:50 2009-05-05T16:37:01 2010-09-16T11:13:14 2010-09-15T15:02:35 2012-02-16T21:52:08 2007-10-16T09:57:09 2007-10-16T09:50:31 2010-08-23T13:04:42 2010-09-16T14:13:21 2009-06-16T16:50:58 2010-09-01T14:29:10 2007-11-13T09:18:02 2007-07-02T16:46:00 2007-06-05T08:33:16 2012-02-16T21:43:46 2007-06-05T08:47:56 2010-09-16T13:02:43 2010-09-23T14:03:24 2010-09-22T11:27:10 2007-10-30T08:24:58 2007-10-30T11:32:55 2007-09-28T07:25:01 2007-06-25T13:07:07 2007-06-25T14:46:07 2010-09-16T15:29:01 2007-10-29T12:44:32 2007-06-05T09:07:04 2007-10-29T12:59:15 2010-09-22T11:47:06 2009-05-05T16:05:09 2012-05-09T13:31:59 2012-05-09T14:08:12 2012-02-16T21:55:54 2010-09-16T14:49:44 2009-05-06T14:34:29 2007-07-02T17:46:41 2010-07-29T11:47:52 2007-10-16T11:08:32 2010-09-01T14:06:24 2009-09-22T19:37:07 2007-06-05T14:32:49 2007-10-29T12:36:05 2010-09-22T13:58:46 2009-06-12T19:20:37 2007-05-16T15:02:11 2007-05-29T14:58:01 2007-05-29T15:23:02 2007-09-25T07:59:50 TRIAZOLAM (object) - DILTIAZEM (precipitant) 10 0.06 0.00025 TRIAZOLAM (object) - FLUCONAZOLE (precipitant) 12 0.00025 0.1 MIDAZOLAM (object) - CLARITHROMYCIN (precipitant) 19 0.008 0.5 MIDAZOLAM (object) - CLARITHROMYCIN (precipitant) 0.5 0.004 16 MIDAZOLAM (object) - ITRACONAZOLE (precipitant) 9 0.0075 0.2 LOVASTATIN (object) - ITRACONAZOLE (precipitant) 10 0.1 0.04 ALPRAZOLAM (object) - FLUOXETINE (precipitant) 0.001 11 0.02 RISPERIDONE (object) - VENLAFAXINE (precipitant) 0.001 0.15 24 ATORVASTATIN (object) - ITRACONAZOLE (precipitant) 0.02 0.2 18 TRIAZOLAM (object) - NEFAZODONE (precipitant) 0.00025 0.2 12 ESCITALOPRAM (object) - CIMETIDINE (precipitant) 0.02 0.8 16 SIMVASTATIN (object) - KETOCONAZOLE (precipitant) 19 0.04 0.4 THEOPHYLLINE (object) - CIMETIDINE (precipitant) 1.2 7 0.35 MIDAZOLAM (object) - FLUCONAZOLE (precipitant) 12 0.0075 0.2 MIDAZOLAM (object) - FLUCONAZOLE (precipitant) 9 0.0075 0.4 THEOPHYLLINE (object) - DULOXETINE (precipitant) 0.12 0.1975 28 ESCITALOPRAM (object) - OMEPRAZOLE (precipitant) 16 0.03 0.02 ZOLPIDEM (object) - KETOCONAZOLE (precipitant) 0.4 0.005 12 PROPAFENONE (object) - FLUOXETINE (precipitant) 0.02 0.4 9 TRIAZOLAM (object) - ERYTHROMYCIN (precipitant) 16 0.333 0.0005 FLUVASTATIN (object) - FLUCONAZOLE (precipitant) 12 0.04 0.2 MIRTAZAPINE (object) - PAROXETINE (precipitant) 20 0.04 0.03 TRIAZOLAM (object) - CLARITHROMYCIN (precipitant) 12 0.000125 0.5 ZIPRASIDONE (object) - CIMETIDINE (precipitant) 0.04 0.8 10 LANSOPRAZOLE (object) - FLUVOXAMINE (precipitant) 18 0.06 0.05 LANSOPRAZOLE (object) - FLUVOXAMINE (precipitant) 0.05 0.06 18 BUPROPION (object) - CLOPIDOGREL (precipitant) 12 0.075 0.15 DESIPRAMINE (object) - FLUOXETINE (precipitant) 0.02 0.05 9 DESIPRAMINE (object) - FLUOXETINE (precipitant) 0.05 0.06 TRIAZOLAM (object) - KETOCONAZOLE (precipitant) 0.4 9 0.00025 TRIAZOLAM (object) - KETOCONAZOLE (precipitant) 0.2 9 0.000125 PALIPERIDONE (object) - PAROXETINE (precipitant) 50 0.003 0.02 MIDAZOLAM (object) - NEFAZODONE (precipitant) 0.01 10 0.2 MIDAZOLAM (object) - KETOCONAZOLE (precipitant) 9 0.0075 0.4 QUETIAPINE (object) - CIMETIDINE (precipitant) 1.2 0.45 7 SIMVASTATIN (object) - DILTIAZEM (precipitant) 0.02 10 0.12 MIRTAZAPINE (object) - CIMETIDINE (precipitant) 1.6 0.03 12 DULOXETINE (object) - FLUVOXAMINE (precipitant) 14 0.06 0.1 DULOXETINE (object) - FLUVOXAMINE (precipitant) 0.06 0.1 VENLAFAXINE (object) - TERBINAFINE (precipitant) 12 0.25 0.075 PAROXETINE (object) - TERBINAFINE (precipitant) 0.125 12 0.02 DESIPRAMINE (object) - SERTRALINE (precipitant) 9 0.05 0.05 DESIPRAMINE (object) - SERTRALINE (precipitant) 0.05 17 0.05 DESIPRAMINE (object) - SERTRALINE (precipitant) 0.15 6 0.05 TOLBUTAMIDE (object) - FLUVOXAMINE (precipitant) 0.15 14 0.5 MEXILETINE (object) - FLUVOXAMINE (precipitant) 6 0.2 0.1 OMEPRAZOLE (object) - FLUVOXAMINE (precipitant) 10 0.02 0.02 MIDAZOLAM (object) - ERYTHROMYCIN (precipitant) 12 0.015 0.5 ATORVASTATIN (object) - ERYTHROMYCIN (precipitant) 0.5 0.01 11 LANSOPRAZOLE (object) - CLARITHROMYCIN (precipitant) 0.8 0.06 18 CLOZAPINE (object) - FLUVOXAMINE (precipitant) 9 0.1 0.05 TRAZODONE (object) - CLARITHROMYCIN (precipitant) 10 0.5 0.05 ROSUVASTATIN (object) - ITRACONAZOLE (precipitant) 14 0.08 0.2 ALPRAZOLAM (object) - ITRACONAZOLE (precipitant) 0.2 10 0.0008 PRAVASTATIN (object) - CLARITHROMYCIN (precipitant) 15 0.04 0.5 ATORVASTATIN (object) - CLARITHROMYCIN (precipitant) 36 0.01 0.5 VENLAFAXINE (object) - CIMETIDINE (precipitant) 0.8 0.15 18 ESCITALOPRAM (object) - ARIPIPRAZOLE (precipitant) 17 0.01 0.01 QUINIDINE (object) - FLUVOXAMINE (precipitant) 0.1 0.2 6 ALPRAZOLAM (object) - KETOCONAZOLE (precipitant) 17 0.001 0.2 ALPRAZOLAM (object) - KETOCONAZOLE (precipitant) 0.001 7 0.2 PRAVASTATIN (object) - ITRACONAZOLE (precipitant) 0.04 18 0.2 ALPRAZOLAM (object) - ERYTHROMYCIN (precipitant) 0.0008 0.4 12 SIMVASTATIN (object) - ERYTHROMYCIN (precipitant) 0.5 12 0.04 OLANZAPINE (object) - FLUOXETINE (precipitant) 15 0.06 0.005 TRIAZOLAM (object) - ITRACONAZOLE (precipitant) 0.2 9 0.00025 ATORVASTATIN (object) - CLARITHROMYCIN (precipitant) 0.08 15 0.5 TRIAZOLAM (object) - ITRACONAZOLE (precipitant) 0.00025 0.2 10 THEOPHYLLINE (object) - FLUVOXAMINE (precipitant) 0.1 12 0.3 DESIPRAMINE (object) - PAROXETINE (precipitant) 0.05 17 0.02 DESIPRAMINE (object) - PAROXETINE (precipitant) 0.03 0.05 DESIPRAMINE (object) - PAROXETINE (precipitant) 0.1 0.02 VENLAFAXINE (object) - DIPHENHYDRAMINE (precipitant) 0.0375 0.1 QUETIAPINE (object) - ERYTHROMYCIN (precipitant) 19 1.5 0.4 VENLAFAXINE (object) - ARIPIPRAZOLE (precipitant) 0.075 27 0.02 MIDAZOLAM (object) - DILTIAZEM (precipitant) 0.06 0.00015 9 ZOLPIDEM (object) - ITRACONAZOLE (precipitant) 0.2 0.01 10 ALPRAZOLAM (object) - NEFAZODONE (precipitant) 0.2 48 0.001 RISPERIDONE (object) - VERAPAMIL (precipitant) 0.24 12 0.001 ALPRAZOLAM (object) - FLUOXETINE (precipitant) 16 0.04 0.002 PRAVASTATIN (object) - ITRACONAZOLE (precipitant) 0.04 104 0.2 PRAVASTATIN (object) - ITRACONAZOLE (precipitant) 0.2 10 0.04 ZOLPIDEM (object) - ITRACONAZOLE (precipitant) 0.005 11 0.2 ALPRAZOLAM (object) - NEFAZODONE (precipitant) 0.002 0.4 16 Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4., Fang JBourin MBaker GB; 1999/02/27 00:00. pubmed Id: 10048600. 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Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam., Yasui NKondo TOtani KFurukori HKaneko SOhkubo TNagasaki TSugawara K; 1998/10/23 00:00. pubmed Id: 9784084. Psychopharmacology (Berl). Last Accessed: 10/09/2015. Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men., Macias WLBergstrom RFCerimele BJKassahun KTatum DECallaghan JT; 1998/12/17 00:00. pubmed Id: 9855322. Pharmacotherapy. Last Accessed: 10/09/2015. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole., Greenblatt DJvon Moltke LLHarmatz JSMertzanis PGraf JADurol ALCounihan MRoth-Schechter BShader RI; 1999/01/01 00:00. pubmed Id: 9871431. Clin Pharmacol Ther. Last Accessed: 10/09/2015. Route of administration: oral study duration: 1 day pretreatment with diltiazem given 3x/day @ 60mg PO. On day two .25mg triazolam was given PO population: 10 subjects, male: 3 female: 7 ages: 18-31 AUC_i/AUC 0-time of measurement (17hrs): 36.0/12.7 = 2.835 AUC_i/AUC 0 -inf: 47/13.9 = 3.381 None None Route of administration: oral study duration: 40mg of simvastatin to establish baseline given two seperate times with a one day gap; after a &gt;1 week washout period participants were given 10 days treatment ketoconazole 40mg 1x/day. 40mg of simvastatin was given during this phase once on day 6 and once on day nine. population: 19 (20 - 1 dropout) 9 male, 10 women ages:30-47 AUC_i/AUC (0 to infinity):12.55 description: This study used an open-label, fixed-sequential, 3-way crossover study design. Nineteen subjects received oral doses of 0.075 mg/kg midazolam and 40 mg simvastatin during 3 phases (baseline, after inhibition with 400 mg ketoconazole for 10 days, and after induction with 600 mg rifampin [INN, rifampicin] for 9 days). Serial plasma concentrations of midazolam and simvastatin were obtained. Oral clearances of midazolam and simvastatin were compared. RESULTS: Oral midazolam clearance decreased after pretreatment with ketoconazole (from a geometric mean of 25 mL x min(-1) x kg(-1) [range, 12-57 mL x min(-1) x kg(-1)] to 2.7 mL x min(-1) x kg(-1) [range, 1.2-8.5 mL x min(-1) x kg(-1)], P &lt; .001) None None None None Route of administration: oral polymorphic enzyme: NO study duration: 1 day petreatment with clarithromycin, single dose of triazolam population: 6 male, 6 female ages:21-39 AUC_i/AUC: 28.9/5.5ng/Ml*h In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin....The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. None None Route of administration: oral study duration: four days pre-treatment with ketoconazole population: male: 2 female: 7 ages: 19-26 NOTE: AUC data taken from table 1 Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double-blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration-time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase. NOTE: The AUC_i/AUC value is for the group that took 150mg of fluvoxamine and is calculated from Table I. route of administration: oral study duration: 5 days population: 14 healthy volunteers, all male tested for known CYP450 polymorphisms? NO ages: 21-30 description: SUBJECTS: The study was carried out as an open, randomized, crossover design. The participants were 14 volunteers; all of the participants were men with a median age of 26 years (range, 21 to 30 years). The subjects had no known heart, liver, or kidney disease according to a clinical examination, clinical chemical and hematologic screening, and electrocardiogram. No participants consumed alcohol or drugs on a regular basis at the time of the study. The volunteers consented to participate in the study on the basis of oral and written information. METHODS: The study was divided into two periods. In period A, all volunteers took 500 mg of tolbutamide (Tolbutamide “DAK”, Nycomed Denmark, Roskilde, Denmark) as a single oral dose. In period B, the volunteers were randomly assigned to two fluvoxamine groups. One group took 150 mg/d of fluvoxamine (Fevarin 100-mg tablets, Solvay Duphar BV, Weesp, The Netherlands) for 5 days with a single oral dose of 500 mg of tolbutamide. The other group took a dose of 75 mg of fluvoxamine for 5 days and a single oral dose of 500 mg of tolbutamide. Period A and period B were separated by at least 1 week. Fluvoxamine was given at 20.00 hours. RESULTS: Total tolbutamide (TB) clearance (CL_TB) was calculated as follows: CL_TB = Dose/AUC in which AUC is the area under the plasma concentration-time curve calculated by means of the trapezoidal rule with extrapolation from the last measurable concentration to infinity. Complete absorption of tolbutamide from the intestine was assumed. The mean plasma concentration of tolbutamide versus time after a single oral dose of 500 mg of tolbutamide before (period A) and during (period B) concomitant intake of 150 mg/d or 75 mg/d of fluvoxamine is shown in Fig 2. The results of the pharmacokinetic analysis are listed in Table I. Thus the median values of the total clearance of tolbutamide were 845 and 962 mL/h in the group that received 75 mg and the group that received 150 mg, respectively, before the administration of fluvoxamine. During fluvoxamine intake, the clearance values decreased to 688 and 642 mL/h, respectively, and the decrease was statistically significant both in the group that received 75 mg and in the entire group (75 mg and 150 mg) but not in the group that received 150 mg alone. The picture was even more clear for the hydroxylation clearance, for which there was a statistically significant reduction as judged from 95% confidence intervals for the median difference not comprising zero both in the 75-mg and 150-mg fluvoxamine groups. There was a tendency toward a more marked reduction in the latter group, although the difference between the two groups (150 mg versus 75 mg in period B) did not reach a level of statistical significance (Table I). See Table I and the equation CL_TB = Dose/AUC for more information. The AUC_i/AUC for the 150mg dose was 1.50 and for the 75mg dose was 1.22. None None None None Quote: In a clinical study, ketoconazole (200 mg BID) increased the area under the concentration vs. time curve (AUC) of PRISTIQ (400 mg single dose) by about 43% and Cmax by about 8%. Concomitant use of PRISTIQ with potent inhibitors of CYP3A4 may result in higher concentrations of PRISTIQ. Route of administration: oral study duration: 5 days pre-treatment with atorvastatin then 3 days atorvastatin and clarithromycin population: 36 from which 12 were randomly chosen to receive clarithromycin, 12 to receive azithromycin, and 12 to receive placebo the study male: 16 or 17 female: 19 or 20 (data appears incorrect in paper) ages: 24-33 AUC_i/AUC: 151.5/83.3ng/h/ml This study investigated the potential for azithromycin and clarithromycin to inhibit the metabolism of atorvastatin. Although there was no interaction between azithromycin and atorvastatin, clarithromycin did have a significant effect on atorvastatin pharmacokinetic parameters. When coadministered, clarithromycin raised subject exposure (AUC24) by 82% and peak plasma concentrations by 56%. These data suggest that while azithromycin appears to be safe to coadminister with atorvastatin, clarithromycin should be avoided in patients taking this and similarly metabolized HMG-CoA inhibitors. None None None None oute of administration: oral polymorphic enzyme: NO study duration: 7 days atorvastatin only, 8 days atorvastatin and clarithromycin dose: .050g atorvastatin1xday .5g clarithromycin 2xday population: 45 men and women (only 15 received atorvastatin) ages:18-60 (mean AUC_i)/(mean AUC) = 113/21 description: Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). &quot;When alprazolam (1 mg BID) and nefazodone (200 mg BID) were coadministered, steady-state peak concentrations, AUC and half-life values for alprazolam increased by approximately 2-fold. Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam is coadministered with nefazodone, a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for nefazodone.&quot; None None Route of administration: oral study duration: read description below population: 48 male volunteers ages: mean(std dev): 26(6.7) Day 7 Alprazolam AUC_i/AUC (0-inf): 1.987 Day 7 4-OH-Alprazolam AUC_i/AUC (0-inf): .71 Description: This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and alprazolam after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in 48 healthy male volunteers. A group of 12 subjects received either placebo twice daily, 1 mg of alprazolam twice daily, 200 mg of nefazodone twice daily, or the combination of 1 mg of alprazolam and 200 mg of nefazodone twice daily for 7 days. Serial blood samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of alprazolam and its metabolites alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (4OH) and nefazodone and its metabolites hydroxynefazodone (HO-nefazodone), m-chlorophenylpiperazine (mCPP), and a triazole dione metabolite (dione) by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for alprazolam, 4OH, nefazodone, HO-nefazodone, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that at steady state, alprazolam Cmax and AUCtau values significantly increased approximately twofold and 4OH Cmax and AUCtau values significantly decreased by 40 and 26%, respectively, when nefazodone was coadministered with alprazolam. There was no effect of alprazolam on the single-dose or steady-state pharmacokinetics of nefazodone, HO-nefazodone, or dione after the coadministration of alprazolam and nefazodone. None None Route of administration: oral study duration: open label cross-over study involving three other antidepressants with at least a 7 day washout period between study arms. In the nefazodone arm, participants received 200mg bid for 3 days then 400mg bid for 5 days. Participants received 2mg of alprazolam on day 1 and the last day of nefazodone treatment. population: 16 male ages: 24-40 AUC_i/AUC (0-inf): 1.47 None None Route of administration: oral study duration: 4 days pretreatment with oral fluconazole 100mg; on day 4 a single oral dose of .25mg triazolam population: 12 male: 2 female: 10 (8 used oral contraceptives) ages: 19-31 AUC_i/AUC (0 to infinity): 30 / 12.2 = 2.46 None None &quot;Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold.&quot; None None Route of administration: oral study duration: This study looked at the interaction between 3 herbal suplements and midazolam. For inhibition/induction controls, they included two rounds in their study where they looked at the interaction of clarithromycin or rifampin and midazolam. Between every round of their study there were 30 days washout and participants were randomized to treatment order but not treatment. The evidence from the clarithromycin round is used here. All 19 participants were given a single oral dose of 8mg midazolam; 24 hours later they started 500mg bid of clarithromycin for 7 days; on day 7 they were given 500mg bid of clarithromycin. population: 19 male: 10 female: 9 ages: mean (STD DEV)= 28 +/- 6 AUC_i/AUC (0 - inf): 752 / 89.6 = 8.45 None None Route of administration: oral study duration: This was a non-random, fixed order, study. Participants received a simultaneous dose of .05mg/kg of IV midazolam and 4mg of oral midazolam to collect baseline data. 24 hours later 500mg bid of oral clarithromycin was given to participants for 7 days. On the last day .05mg/kg of IV midazolam and 4mg of oral midazolam was administered after the last dose of clarithromycine population: 16 : 8 male, 8 female ages: 30-38 AUC_i/AUC (radiolabeled oral): 336/48 = 7 None None None None Route of administration: oral study duration: four days pre-treatment with itraconazole population: male: 2 female: 7 ages: 19-26 NOTE: AUC data taken from table 1 AUC_i/AUC:42/3.9 Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double-blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration-time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase. Route of administration: oral study duration: 4 dys pre-treatment with 100mg oral itraconazole or placebo; on day 4 a single 40mg dose of oral lovastatin was given population: 10 male: 8 female: 2 ages: 19-24 AUC_i/AUC (total): 222 / 15 = 14.8 NOTE: placebo AUC could not be accurately measured but was known to be lower than 15ng/ml*h None None route of administration: oral study duration: at least 27 days population: 11 subjects tested for known CYP450 polymorphisms? NO ages: none given description: SUBJECTS: 11 subjects received fluoxetine treatment (n = 4 placebo first, n = 7 alprazolam first). METHODS: The study had a within-subject, double-blind, placebo-controlled, parallel design. Subjects attended 4 study sessions; the first 2 study sessions occurred in the absence of SSRI medications, while the final 2 sessions occurred after a minimum of 21 days of administration of SSRI medication (citalopram 20 mg or fluoxetine 20 mg). Study sessions took place at least 3 days apart. At each study session, subjects were randomly assigned to a single oral dose of alprazolam (1 mg) or placebo at 9:00 am in the morning (ie, 1 of each for the 2 sessions before SSRI administration and 1 of each for the final 2 sessions after SSRI administration). During the post-SSRI study sessions, daily SSRI dosing was continued, while blood samples were collected up to 48.0 hours (ie, SSRIs were administered at 24.0 and 48.0 hours after single-dose alprazolam administration). Trough citalopram, fluoxetine, and metabolite serum concentrations were determined on 5 occasions: on days 1 and 7 of SSRI administration, prior to alprazolam/placebo administration at study sessions 3 and 4, and 7 days after discontinuation of study medications. During the study sessions, a small standardized breakfast (bagel and apple juice) was provided 1 hour postalprazolam administration, and a sandwich and apple juice was provided 4 hours postalprazolam administration. From 8 hours postalprazolam administration, food intake was not regulated. Subjects were instructed not to consume grapefruit juice during the study due to the potential for inhibition of the CYP3A4 enzyme. RESULTS: Coadministration with fluoxetine significantly increased alprazolam AUC for all time intervals: 0-3 hours (P &lt; 0.05), 0-8 hours (P &lt; 0.005), 0-48 hours (P &lt; 0.001), and 0-inf ( P &lt; 0.001) (Table 2 and Fig. 1). The AUC 0-inf increased by 31.8% postfluoxetine. None None NOTE: The precip_dose is the dose from days 8-14 route of administration: oral study duration: 15 days population:24 healthy volunteers (18 male, 6 female) tested for known CYP450 polymorphisms? NO ages: 19-45 description: SUBJECTS: Thirty healthy male (22) and female (8) volunteers participated in the study. Informed consent was obtained for all subjects. Mean (range) age, weight, and height for the subjects were 29.6 years (19-45 years), 78.3 kg (46-102 kg), and 179 cm (158-198 cm), respectively. Twenty-eight of the 30 enrolled subjects completed the study. Two male subjects withdrew their consent, one on Day 8 during a morning clinic visit and the other on Day 12 before the morning dose of venlafaxine. Pharmacokinetic and pharmacodynamic data were evaluated for only 24 subjects. Four subjects were excluded from the analyses because of protocol violations. Two male subjects did not collect complete 96-hour urine samples, and 2 female subjects consumed xanthene-containing foods or beverages during the study. METHODS: This was an open-label drug interaction study to evaluate the effects of steady-state venlafaxine on the pharmacokinetic disposition of single oral doses of risperidone. Single 1 mg doses of risperidone (1 mg Risperdal® tablet, Janssen Pharmaceutica, Titusville, NJ) were administered on Days 1 and 11 with 180 mL of room-temperature water at approximately 10 a.m. following an overnight fast. Multiple doses of venlafaxine (37.5 mg and 75 mg Effexor® tablets, Wyeth-Ayerst Laboratories, Radnor, PA) were administered as follows: 37.5 mg bid from Days 5 through 7 and then 75 mg twice daily from Days 8 through 14. Venlafaxine doses were administered with approximately 240 mL of room- temperature water at 8 a.m. and 8 p.m. with food (except during the designated fasting period on Day 11). Single-dose pharmacokinetic profiles of risperidone and 9-hydroxyrisperidone and the total active moiety were evaluated on Days 1 through 5 (risperidone alone) and on Days 11 through 15 (risperidone plus venlafaxine). RESULTS: Risperidone mean oral clearance decreased by 38% (885 +/- 707 mL/min vs. 550 +/- 406 mL/min), and volume of distribution decreased by 17% (215 +/- 91 L vs. 178 +/- 66 L), resulting in a 32% increase in mean AUC_(0–inf) (35.3 +/- 32.1 ng x h/mL vs. 46.7 +/- 31.1 ng x h/mL) and a 29% increase in mean C_max (5.33 +/- 2.15 ng/mL vs. 6.89 +/- 2.96 ng/mL) with venlafaxine coadministration. Both risperidone AUC_(0–inf) and C_max failed to meet bioequivalence criteria (90% CI = 134%-167% and 117%-143%, respectively). None None None None Route of administration: oral study duration: 13 days population: 18 participants; 5 male, 5 female ages:18-45 dose: 20mg of atorvastatin on day one, three days no drug, days 6-10 participants were given 200mg itraconazole 1xday for 5 days, on day 10 a portion of the participants were given a single dose of 20 mg atorvastatin. PK parameters were measured followed for another three days (mean AUC_i)/(mean AUC) = 246.7/98.7 (AUC is 0-infinity) description: n this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites. RESULTS: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P &lt; .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P &lt; .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P &lt; .05). Cimetidine - In subjects who had received 21 days of 40 mg/day Celexa, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. None None &quot;When a single oral 0.25 mg dose of triazolam was coadministered with nefazodone (200 mg BID) at steady state, triazolam half-life and AUC increased 4-fold and peak concentrations increased 1.7-fold. Nefazodone plasma concentrations were unaffected by triazolam. Coadministration of nefazodone potentiated the effects of triazolam on psychomotor performance tests. &quot; None None Route of administration: oral study duration: 2 days treatment w/ triazolam (TRZ) alone (.25mg 1xday) followed by 7 days treatment with nevazodone alone (200mg, bid); followed by two days dosing with nevazodone + TRZ population: 12 male ages:23-38 &quot; Mean triazolam peak concentration values increased (p = 0.003) from 2.33 to 3.88 ng/ml when triazolam was administered alone and in combination with nefazodone, respectively. Corresponding mean triazolam area under the curve values increased (p &lt; 0.001) from 8.14 to 31.74 ng.h/ml.&quot; None None None None route of admininistration: oral study duration: 5 days population: 16 healthy subjects (12 male, 4 female) from the UK; 14 Caucasian, 2 of African ancestry tested for known CYP450 polymorphisms? Yes -- CYP2D6 and CYP2C19 genotyping -- 1 CYP2D6 poor metabolizer ages: 18-45 description: SUBJECTS: 16 healthy subjects (18-45 years; 12 male and four female (14 Caucasian and two black subjects) in the cimetidine study were recruited in the UK. CYP2D6 and CYP2C19 [genotyping] were determined according to standard methods. The results were only used to aid interpretation of the pharmacokinetic results. STUDY DESIGN: Sixteen subjects were administered cimetidine (400 mg twice daily) or placebo for 5 days. On the morning of day 4, a single dose of 20 mg escitalopram was administered. The wash-out period was 3 weeks between the treatments. RESULTS: Cimetidine (400 mg twice daily) caused a significant increase of 72% in the AUC(0-inf) for escitalopram given as a single oral dose. A single CYP2D6 poor metabolizer was identified in each of the two studies. However, the results from these subjects were within the ranges of those from the other subjects. NOTE: The object dose is the dose of aminophylline and is equivalent to 0.2765 g of anhydrous theophylline. The AUC_i/AUC is from table 2. route of administration: iv (object), oral (precip) study duration: 9 days population: 7 healthy subjects (all male); 5 smokers, 2 nonsmokers tested for known CYP450 polymorphisms? NO ages: 25-44 description: SUBJECTS: 7 subjects in group 2 (5 smokers, 2 nonsmokers) age ranged from 25-44 (mean 34 +/- 8.3yrs.) and weight from 69.9-81.2 kg (mean 74.0 +/- 4.2 kg). Eighty-four percent of subjects were smokers. Sixty-three percent were Caucasian and 37% were African-American. METHODS: A two-way, randomized, crossover study was performed to assess the pharmacokinetics of theophylline administered with placebo or after administration of 9 days of dosing with either olanzapine or cimetidine. Subjects were divided into two groups. Group 1 received theophylline after olanzapine or placebo and group 2 received theophylline after cimetidine or placebo. Cimetidine (Tagamet) 400 mg orally 3 times/day was administered approximately every 8 hours for 9 days (27 total doses). Placebo was administered in the same manner as cimetidine or olanzapine, corresponding to study group. Aminophylline was admininstered as a single intravenous dose of 350 mg over 30 minutes on the last day of each treatment period, 1 hour after the morning dose of olanzapine, cimetidine or placebo. This dose is equivalent to 276.5 mg of anhydrous theophlline. RESULTS: Administration of aminophylline with cimetidine resulted in a statistically significant increase in theophylline AUC and half-life. None None None None Quote: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, crossover study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. Route of administration: oral study duration: randomized cross-over design; participants given placebo or 400mg fluconazole on day 1 and 200mg days 2 to 6. A single dose of 7.5mg oral MDZ was given on day 1 and day 6 while .05mg/kg of IV MDZ was given on day 4. population: 12 healthy volunteers, 7 male, 5 female ages: 19-25 Day 1 (AUC is 0-infinity) AUC_i/AUC = 3.513 Day 6 (AUC is 0-infinity) AUC_i/AUC = 3.6 None None Route of administration: oral study duration: a single dose of 400mg oral fluconazole followed by a single dose of 7.5mg midazolam 60 minutes later population: 4 female and 5 male ages: 19-25 AUC_i/AUC (0-inf):421/113 = 3.726 NOTE: The study shows a decrease in the ratio of 1-OH-MDZ to MDZ in the presence of fluconazole indicating that less of the parent is being converted to metabolite description: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, alpha-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. RESULTS: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. None None NOTE: The AUC_i/AUC is from the combined male and female study results. The object dose was given intravenously as a 250 mg dose of aminophylline over 30 minutes. route of administration: oral (duloxetine)/IV (theophylline) study duration: 5 days population: 28 healthy non-smokers (10 male, 18 female) tested for known CYP450 polymorphisms? No ages: 18-55 description: In the nonsmoking men-only study, 10 of 11 subjects completed the study. One subject was withdrawn because of reports of several adverse events (cause not documented) before receiving the study drug. The mean (+/-SD) age of the subjects was 33 +/- 9 years, the mean height was 174.2 +/- 7.2 cm, the mean bodyweight was 73.9 +/- 9.3 kg and the mean BMI was 24.3 +/- 2.0 kg/m2. All subjects were Caucasian. In the nonsmoking women-only study, 18 of 20 subjects completed the study. Two subjects were withdrawn; one had mild to moderate adverse events related to duloxetine administration, and the other, who received only placebo, had poor venous access. The mean (+/-SD) age of the subjects was 38.2 +/- 9.8 years, the mean height was 166.5 +/- 7 cm, the mean bodyweight was 75.3 +/- 10 kg and the mean BMI was 27.1 +/- 2.8 kg/m2. Sixty percent of the subjects were Caucasian and the rest were African American. METHODS: The separate studies in women and men were designed identically as single-centre, subject-blind, randomized, two-way, two-period, balanced crossover studies. Duloxetine was administered in a subject-blind manner, but the infusion of aminophylline was open-label. In each period, duloxetine 60 mg and placebo were given orally twice daily on days 1–4 and once on the morning of day 5. On day 5, theophylline 197.5 mg was given as a 30-minute intravenous infusion of aminophylline 250 mg. Each aminophylline dose was separated by at least 17 days. RESULTS: In men, the presence of duloxetine was associated with a small, statistically insignificant increase of 7% in the theophylline C_max and the AUC_inf (table IV). However, in women, there was a statistically significant increase in the theophylline C_max (9%) and the AUC_inf (20%). When the results from both men and women were combined, there was a statistically significant increase in the theophylline AUC_inf (13%) but not in the C_max (7%). Nonetheless, the change in the theophylline AUC_inf in the presence of duloxetine was small, and the 90% CI was within the 0.8–1.25 equivalence range for men, and for men and women combined, but narrowly missed the upper boundary of the equivalence range in women (0.8–1.27). None None None None route of admininistration: oral study duration: 6 days population: 16 healthy subjects (8 male, 8 female) from the UK; 15 Caucasian, 1 of African ancestry tested for known CYP450 polymorphisms? Yes -- CYP2D6 and CYP2C19 genotyping -- 1 CYP2D6 poor metabolizer ages: 18-45 description: SUBJECTS: 16 healthy subjects (18-45 years; eight male and eight female (15 Caucasian and one black subject) in the omeprazole study were recruited in the UK. CYP2D6 and CYP2C19 [genotyping] were determined according to standard methods. The results were only used to aid interpretation of the pharmacokinetic results. STUDY DESIGN: Sixteen subjects were administered omeprazole (30 mg once daily) or placebo for 6 days. On the morning of day 5, a single dose of 20 mg escitalopram was administered. The wash-out period was 3 weeks between the treatments. RESULTS: Omeprazole (30 mg once daily) caused a significant increase (+51%) in the AUC(0-inf) for escitalopram given as a single 20 mg oral dose. A single CYP2D6 poor metabolizer was identified in each of the two studies. However, the results from these subjects were within the ranges of those from the other subjects. None None Quote: Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown. route of administration: oral study duration: two days population: 12 healthy volunteers (8 male, 4 female); non-smokers tested for known CYP450 polymorphisms? N/A ages: 20 - 40 description: Twelve healthy volunteers (8 men and 4 women), aged 20 to 40 years, participated after giving written informed consent. All were active ambulatory non-smoking adults, with no evidence of medical disease and taking no other medications. Female subjects were not taking oral contraceptives and did not have contraceptive implants. The study had a double-blind, randomized, 5-way crossover design, with at least 7 days elapsing between treatments. Medications were separately and identically packaged in opaque capsules and administered orally. At 8 AM on study day 1, subjects entered the outpatient Clinical Psychopharmacology Research Unit where they received the initial dose of azole (or placebo) and remained under observation for 30 minutes. Subjects took a second dose of azole (or placebo) at home at 4 PM on day 1. On the morning of day 2, after ingesting a standardized light breakfast with no caffeine-containing food or beverages and no grapefruit juice, they returned to the Research Unit at approximately 7:30 AM. They fasted until 12 noon, after which they resumed a normal diet (without grapefruit juice or caffeine-containing food or beverages). The third dose of azole (or placebo) was given at 8 AM, and the single dose of zolpidem or placebo was given at 9 AM. A final azole (or placebo) dose was given at 5 PM. Coadministration of zolpidem with ketoconazole (treatment C) significantly prolonged zolpidem elimination half-life, increased total AUC, and decreased apparent oral clearance when compared to zolpidem plus placebo (treatment B; Figure 3 and Table II). Zolpidem AUC during treatment C was increased by a factor of 1.83 + 0.24 (mean +/- SE) compared to treatment B values, and clearance during treatment C was reduced to 64% +/- 7% of treatment B values. None None NOTE: The AUC_i/AUC value given is for the r-propafenone enantiomer and calculated from Table I. route of administration: oral study duration: 10 days population: 9 healthy Chinese volunteers (7 male, 2 female), all nonsmokers and non-drinkers tested for known CYP450 polymorphisms? YES -- CYP2D6 phenotyping - All classified as extensive metabolizers ages: 24-46 description: SUBJECTS: Nine healthy Chinese volunteers (seven men and two women) were included in the study. The ages ranged from 24 to 46 years and their weights ranged 50 to 75 kg. All subjects were healthy as assessed by a physical examination, an ECG, and blood biochemistry testing. None of the subjects smoked tobacco or drank alcohol. All subjects abstained from drugs for at least 2 weeks before and during the study. Subjects were excluded if they were receiving any medications known to induce or inhibit cytochrome P450. Pregnant women were excluded by a test for serum human chorionic gonadotropin. This study was approved by the Ethics Committee of Nanjing Medical University (Nanjing, China). Written informed consent was obtained from all subjects. CYP2D6 phenotype: The urinary molar metabolic ratio (MR) of the subjects was calculated by use of the equation: [MR = Dextromethorphan (mg/L)/dextrorphan (mg/L) x 0.948]. Phenotype was determined on the basis of an MR value according to the method of Schmid et al. Any subject with an MR &gt;0.3 was classified as a poor metabolizer; subjects with MR values &lt;=0.3 were classified as an extensive metabolizer. METHODS: The study was divided into two phases. The first phase examined baseline dextromethorphan metabolic phenotyping and baseline pharmacokinetics of propafenone enantiomers. The second phase was a repeat of the first phase except that it was conducted after subjects took 20 mg/day fluoxetine for 10 days. There was at least a 2-week washout period between the two phases. RESULTS: All nine subjects had dextromethorphan MR values &lt;0.3 at baseline and were classified as having an extensive metabolizer phenotype for CYP2D6. The dextromethorphan MR for all subjects remained at less than 0.3 after pretreatment with fluoxetine (20 mg/day) for 10 days. However, there were significant differences of mean MR values before and after fluoxetine therapy (0.028 +/- 0.031 versus 0.080 +/- 0.058; P = .001), indicating a strong inhibition of the CYP2D6 activity by fluoxetine in Chinese subjects. Metabolism of propafenone enantiomers was also impaired significantly after fluoxetine. For S-propafenone, AUC_(0-[infinity]) increased from 2238.3 +/- 725.2 ug x h x L-1 at baseline to 3371.2 +/- 986.7 ug x h x L-1 (P = .001). For R-propafenone, AUC_(0-[infinity]) also increased from 1576.3 +/- 573.1 ug x h x L-1 before fluoxetinetherapy to 2370.7 +/- 704.5 ug x h x L-1 (P = .005). None None Route of administration: oral study duration: 0.5mg oral triazolam was administered alone or after 3 days of pretreatment with .333 mg tid erythromycin population: 16 males (including 5 smokers) ages: 19-42 AUC_i/AUC: 41.4/20.1 = 2.06 None None Route of administration: oral study duration: 4 days pretreatment with oral fluconazole 400mg day 1 and 200mg days 2-4; on day 4 a single oral dose of 40mg fluvastatin population: 12 male: 5 female: 7 ages: 19-26 AUC_i/AUC 0 to infinity: 955 / 520 = 1.837 None None NOTE: AUC_0-24 is used for AUC_i/AUC. route of administration: oral study duration: 27 days population: 20 healthy subjects (11 male, 9 female) tested for known CYP450 polymorphisms? Yes -- CYP2D6 - all were extensive metabolizers ages: 18-45 description: SUBJECTS Twelve healthy male and twelve healthy female subjects aged between 18 and 45 years participated in this three-period crossover study. They were extensively screened within 3 weeks of study entry and had to be medically and mentally healthy, as evidenced by medical history, full physical examination, routine clinical laboratory investigations and ECG. Their body mass index had to be within the range 19-29 kg/m2 and they were not allowed to be smokers. Subjects were screened for being extensive metabolizers of CYP2D6 using dextromethorphan as a probe. Of the 12 males and 12 female subjects enrolled into the study, three subjects (1 male, 2 females) discontinued the study due to the emergence of adverse events on days 21, 23, and 27, respectively, of the 27 day treatment period. METHODS Subjects meeting the inclusion criteria were enrolled into the study. They were randomly assigned to one of six treatment sequences in this three-period crossover study without washout intervals. They were admitted to the clinical pharmacology institute two days before the start of the study. In order to mimic clinical practice as much as possible, paroxetine was administered in the morning and mirtazapine in the evening, with a 12h interval between administrations. From day 1 up to and including day 26 paroxetine 20 or 40 mg or placebo was administered at 9 a.m. and mirtazapine 15 or 30 mg or placebo at 9 p.m. each day. The treatments used were: (A) 20 mg paroxetine plus one placebo paroxetine capsule at 9 a.m. and two placebo mirtazapine tablets at 9 p.m. for the first three days followed by two 20 mg paroxetine capsules at 9 a.m. and two placebo mirtazapine tablets at 9 p.m. for the following 6 days; (B) two placebo paroxetine capsules at 9 a.m. and one 15 mg mirtazapine plus one placebo mirtazapine tablet at 9 p.m. for 3 days followed by two placebo paroxetine capsules at 9 a.m. and two 15 mg mirtazapine tablets at 9 p.m. for the following 6 days; (C) 20 mg paroxetine plus one placebo paroxetine capsule at 9 a.m. and 15 mg mirtazapine plus one placebo mirtazapine tablet at 9 p.m. for 3 days followed by two 20 mg paroxetine at 9 a.m. and two 15 mg mirtazapine at 9 p.m. for the following 6 days. Thus, six possible treatment sequences (TS1 - TS6) were used (Table 1). In those treatment sequences in which either paroxetine or mirtazapine had also been administered in the preceding treatment sequence, the drug was continued at the highest dose, i.e. two 20 mg capsules for paroxetine and two 15 mg tablets for mirtazapine. Two males and two females were randomized to each of the six treatment sequences. RESULTS Adding paroxetine to mirtazapine treatment increased the mirtazapine plasma concentrations. The AUC_0-24 increased by approximately 17% during concomitant administration of paxoetine. Statistically significant differences were observed in AUC_0-24 and C_max,av. None None route of administration: oral study duration: single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co-administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co-administered with oral Maalox1. population: 11 healthy young subjects, 9 female, 3 male (only 10 completed the cimetidine - ziprasidone study) tested for known CYP450 polymorphisms? ages: 18-45 description: Results The administration of cimetidine increased the ziprasidone AUC(0,inf) by 6% but there were no statistically significant differences in Cmax, tmax or lambda_z between the ziprasidone + cimetidine group and the ziprasidone group. None None route of administration: oral study duration: six days population: 18 healthy subjects (9 male, 9 female) All Japanese tested for known CYP450 polymorphisms? CYP2C19 -- 6 homozygous EMs, 6 heterozygous EMs, and 6 poor metabolizers ages: 21-34 description: NOTE: AUC_I/AUC in the DIKB knowledge-base is from the 6 participants classified as homozygous EMs and the value is for the R-enantiomer. The AUC increase for the S-enantiomer was greater; please see the full text. Eighteen healthy subjects, of whom six each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), or poor metabolizers (PMs) for CYP2C19, participated in the study. Each subject received either placebo or fluvoxamine, 25 mg twice daily for 6 days, then a single oral dose of 60 mg of racemic lansoprazole. The plasma concentrations of lansoprazole enantiomers and lansoprazole sulphone were subsequently measured for 24 h post lansoprazole administration using liquid chromatography. In the homEMs and hetEMs, fluvoxamine significantly increased the AUC(0, inf) and C max and prolonged the elimination half-life of both (R)- and (S)-lansoprazole, whereas in the PMs, the only statistically significant effect of fluvoxamine was on the AUC(0, inf) for (R)-lansoprazole. The mean fluvoxamine-mediated percent increase in the AUC(0, inf) of (R)-lansoprazole in the homEMs compared with the PMs was significant ( P = 0.0117); however, C max did not differ among the three CYP2C19 genotypes. On the other hand, fluvoxamine induced a significant percent increase in both the AUC(0, inf) and C max for (S)-lansoprazole in the homEMs compared with the hetEMs ( P = 0.0007 and P = 0.0125, respectively) as well as compared with the PMs ( P &lt; 0.0001 for each parameter). None None NOTE: AUC_I/AUC in the DIKB knowledge-base is from the 6 participants classified as homozygous EMs. route of administration: oral study duration: six days population: 18 healthy volunteers (9 male, 9 female); All Japanese tested for known CYP450 polymorphisms? Yes -- CYP2C19 - 6 homozygous EMs, 6 heterozygous EMs, 6 homozygous PMs ages: mean 25 years (+/- 3.8) description: Eighteen healthy Japanese volunteers (9 men and 9 women) who were H. pylori-negative were enrolled in this study. Their mean age was 25.1 +/- 3.8 years and mean body weight was 56.6 +/- 13.3 kg. The mutated alleles for CYP2C19, CYP2C19*3(*3), and CYP2C19*2(*2) had been identified using polymerase chain reaction-restriction fragment length polymorphism methods of De Morais et al, before this study. The CYP2C19 genotype analyses revealed 5 different patterns as follows: *1/*1 in 6, *1/*2 in 3, *1/*3 in 3, *2/*2 in 5, and *2/*3 in 1. These were divided into 3 groups, homozygous EMs (*1/*1, n = 6), heterozygous EMs (*1/*2 and *1/*3, n = 6), and PMs (*2/*2 and *2/*3, n = 6). A randomized double-blind placebo-controlled crossover study design in 3 phases was conducted at intervals of 2 weeks. Fluvoxamine (25 mg) as a capsule containing the equivalent of a tablet (Luvox, Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan), or matched placebo was given orally twice a day (9 AM, 9 PM) for 6 days. On day 6, they took a single oral 60-mg dose of lansoprazole (Takepron, Takeda Pharmaceutical Co, Ltd, Osaka, Japan) with 25 mg dose of fluvoxamine, or placebo after overnight fasting (9 AM). Fluvoxamine pretreatment significantly increased AUC_0-24 of lansoprazole by 3.8-fold in homozygous EMs (P&lt;0.01) and 2.5-fold in heterozygous EMs (P&lt;0.05), and prolonged elimination half-life by 3.0-fold in homozygous EMs (P&lt;0.01) and by 1.7-fold in heterozygous EMs (P&lt;0.05), respectively. There were no differences in AUC_0-24 during fluvoxamine treatment among CYP2C19 genotypes. None None route of administration: oral study duration: 4 days population: 12 healthy volunteers (all male); all nonsmokers tested for known CYP450 polymorphisms? No ages: 22-27 description: SUBJECTS: Twelve healthy, nonsmoking male volunteers aged 22 to 27 years (weight range, 67-95 kg; body mass index range, 21-26 kg/m2) participated in this study after having given written informed consent. The subjects were ascertained to be in good health by medical history, a full clinical examination, and standard hematologic and blood chemical laboratory tests before enrollment. METHODS: This study was an open crossover study with 3 phases. Between phases 1 and 2, there was a 1-week-long washout period, and between phases 2 and 3, there was a washout period of 2 weeks. The first phase was a control period, in which all volunteers received a single oral dose of bupropion (Zyban sustained release, 150 mg; GlaxoSmithKline, Uxbridge, United Kingdom). In the second and third phases the volunteers received a 4-day-long oral antiplatelet agent pretreatment in randomized balanced order with either clopidogrel (Plavix, 75 mg once daily; Sanofi Synthelabo, Guildford, United Kingdom) or ticlopidine (Ticlid, 250 mg twice daily; Sanofi Synthelabo). On day 4, 1 hour after the last dose of the antiplatelet agent, a single 150-mg dose of bupropion was administered. Venous blood samples (10 mL each) for determination of bupropion and hydroxybupropion concentrations were taken just before and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours after administration of bupropion. In all phases the volunteers fasted for 8 hours before and 4 hours after administration of bupropion. Identical meals were provided on the 3 study days. Volunteers were also required to refrain from strenuous physical exercise, alcohol- or caffeine-containing drinks, smoking, grapefruit juice, and other medications for 2 days before and after study drug administration. RESULTS: Both of the thienopyridine derivatives had a significant effect on the AUC of bupropion: in the clopidogrel phase, the bupropion AUC increased by 60% (P = .02; 95% CI, 21% to 98%). None None None None Quote: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. None None Route of administration: oral (inferred because IV formulations do not appear to be available for fluoxetine and desipramine) study duration: see below population: 9 healthy males; all extensive metabolizers of dextromethorphan (o-demethylation) ages: mean(std dev): &quot;adults&quot; but no mention of age. It can be inferred that these were healthy male adults and not exclusively elderly or children Description: he pharmacokinetic interactions of sertraline and fluoxetine with the tricyclic antidepressant desipramine were studied in 18 healthy male volunteers phenotyped as extensive metabolizers of dextromethorphan. Concentrations in plasma were determined after 7 days of desipramine (50 mg/day) dosing alone, during the 21 days of desipramine and selective serotonin reuptake inhibitor (SSRI) coadministration (fluoxetine, 20 mg/day; sertraline, 50 mg/day), and for 21 days of continued desipramine administration after SSRI discontinuation. Desipramine Cmax was increased 4.0-fold versus 31% and AUC0-24 was increased 4.8-fold versus 23% for fluoxetine versus sertraline, respectively, relative to baseline after 3 weeks of coadministration. Desipramine trough concentrations approached baseline within 1 week of sertraline discontinuation but remained elevated for the 3-week follow-up period after fluoxetine discontinuation. Concentrations of SSRIs and their metabolites correlated significantly with desipramine concentration changes (for fluoxetine/norfluoxetine, r = 0.94 to 0.96; p &lt; 0.001; for sertraline/desmethylsertraline, r = 0.63; p &lt; 0.01). Thus, sertraline had less pharmacokinetic interaction with desipramine than did fluoxetine at their respective, minimum, usually effective doses. NOTE: THE AUC_i/AUC value is calculated from Table II. route of administration: oral study duration: at least 8 days population: 5 normal white male volunteers tested for known CYP450 polymorphisms? NO ages: 35-53 None None None None Route of administration: oral study duration: four days pre-treatment with ketoconazole population: male: 3 female: 6 ages: 20-26 Ketoconazole increased the mean AUC of triazolam from 5.9ng/ml to 132ng/ml and the Cmax from 1.5 to 4.6ng/ml In a double-blind clinical pharmacokinetic-pharmacodynamic study, administration of triazolam (0.125 mg) preceded by ketoconazole, compared to triazolam preceded by placebo, produced a nearly 9-fold reduction in apparent oral clearance of triazolam (41 vs. 337 ml/min) and a 4-fold prolongation of half-life (13.5 vs. 3.4 hr). NOTE: AUC increase values take from table 3 None None route of administration: oral study duration: 13 days population: 50 healthy subjects (all male) tested for known CYP450 polymorphisms? YES -- CYP2D6 genotyping - all were extensive or ultrarapid metabolizers ages: 18-54 description: SUBJECTS: Sixty men aged 18-55 years were eligible to participate in the study if they had previously been genotyped as CYP2D6 extensive metabolizers or ultrarapid metabolizers of CYP2D6 substrates, on the basis of genetic testing. They were also required to have a body mass index of 18-30 kg/m2, supine blood pressure of 100-140 mmHg systolic/50-90 mmHg diastolic, and to smoke no more than 10 cigarettes, two cigars or two pipes per day. The subjects were considered to be healthy on the basis of physical examination, medical history, 12-lead electrocardiogram (ECG), serum chemistry, and hematology and urinalysis performed during the screening phase. Exclusion criteria included: poor or intermediate CYP2D6 metabolizers, known allergy to study medications, recent history of substance abuse, history of any systemic disease or positive serology (including hepatitis B and C), bradycardia (heart rate &lt; 50 bpm) or consumption of &gt; 450 mg of caffeine per day. No medications (including non-prescription) were permitted during the course of the study, with the exception of acetaminophen (up to 1500 mg/day) for headache, anticholinergic agents for the treatment of emergent EPS and lorazepam for the management of muscle spasm at the investigator’s discretion. Both treatment groups were balanced for demographic characteristics (Table 1). All subjects were male and aged 18-54 years, with the majority being white (75%). Ten subjects (all of whom were randomized to receive the combination of paroxetine and paliperidone ER followed by paliperidone ER alone) discontinued study medication and all in the first period (in which they received the combination regimen). METHODS: This was a single-center, randomized, open-label, single-dose, two-treatment, two-period, crossover study (Fig. 1). The study consisted of three phases: screening, beginning within 21 days before first study drug administration; an open-label treatment phase consisting of two treatment periods; and end-of-study evaluations at study completion or upon withdrawal. Subjects were randomly assigned to one of two treatment-sequence groups (30 subjects per sequence group) according to a computer-generated randomization scheme. During the open-label treatment phase, all subjects received each of the following in order determined by randomization: one tablet of paliperidone ER 3 mg on Day 1 (Treatment A); or paroxetine 20 mg/day on Days 1-13, and one tablet of paliperidone ER 3 mg on Day 10 (Treatment B). Paliperidone ER was administered in the morning (between 07:30-10:00) while subjects were in the fasting state (overnight, for at least 10 h), and subjects continued to fast for 4 h after paliperidone ER administration prior to a standardized meal. On the day that both paroxetine and paliperidone ER were taken, paroxetine was administered in the fasted state 30 min before paliperidone ER; at all other time points, paroxetine was taken with food in the morning. There was a washout period of 14-28 days between paliperidone ER treatments. RESULTS: The 90% CI for the ratio of geometric treatment means was within the conventional no-effect boundaries (80-125%) for C_max, but not for AUC_0-last or AUC_inf (Table 3). However, the higher total exposure to paliperidone following administration of paliperidone ER and paroxetine compared with paliperidone ER alone was not considered clinically relevant, with a ratio of geometric treatment means of 116.48% for AUC_inf (90% CI: 104.49-129.84). None None None None Route of administration: oral study duration: 40 participants were randomized to four groups of 10; one group of 10 received 10mg of MDZ on day followed by a washout of 2 days then participants were titrated to a dose of 200mg bid nefazodone and held at that dose until 12 days total of nefazodone treatment. On day 12 participants received a 10mg dose of MDZ. population: 17 male, 23 female ages:18-50 AUC_i/AUC (0-inf): 1171/257 = 4.56 NOTE: The object dose given is the dose starting the 9th day of the study. The AUC_i/AUC is the comparison between study days 19 and 15. route of administration: oral study duration: 19 days population: 7 subjects with selected psychotic disorders (all male) tested for known CYP450 polymorphisms? NO ages: 21-59 description: SUBJECTS: Thirteen men entered the study (eight were white, four black, and one mixed ethnicity). The mean (range) age, weight, and height of the patients were 37.5 (21–59) years, 86.7 (49–140) kg, and 177.8 (160–193) cm, respectively. Nine men (69.2%) had schizoaffective disorder, three (23.1%) had bipolar disorder, and one (7.7%) had paranoid schizophrenia. Six patients were withdrawn because of lack of efficacy (N = 2), adverse events (N = 2), and refusal to continue (N = 2). All 13 patients were included in the safety analysis, but only the seven patients who completed the entire study were entered into the pharmacokinetic analysis. METHODS: Thirteen men (aged 18–60 years) with selected psychotic disorders were entered into this open-label, non-randomized, escalating-dose, pharmacokinetic trial conducted at a single center. Psychotropic medications were withdrawn on day, 1 and patients underwent a 2-day washout period. On days 3 to 8, patients received quetiapine in escalating doses from 25 to 150 mg three times daily, at approximately 7 a.m., 3 p.m., and 11 p.m. Quetiapine 150 mg three times daily was then administered on days 9 to 18. The final dose was given on the morning of day 19. Cimetidine 400 mg was initiated on the afternoon of day 15 and was administered three times daily with each dose of quetiapine thereafter. RESULTS: The mean plasma concentration versus time profiles for quetiapine determined on days 11, 15, and 19 were similar with a slight increase in the mean plasma concentration during coadministration with cimetidine. Using day 15 as baseline, geometric mean steady-state AUC_0–8h and C_max increased by 24% and 19%, respectively, after coadministration with cimetidine (day 19). Using day 11 as baseline, however, increases of only 10% and 4% were detected. In addition, differences between the 2 baseline days (11 and 15) in mean steady-state AUC_0–8h and C_max were 13% and 14%, respectively (intrasubject variability). The geometric mean quetiapine AUC_0–8h,ss was significantly higher with cimetidine than without compared with day 15 (p=0.002) but not on day 11 (p=0.09). However, variability between the days without cimetidine coadministration (i.e., days 11 and 15) was also significant (p=0.04), with a change of 13% (p=0.04). None None Route of administration: oral polymorphic enzyme: NO study duration: 14 days diltiazem pretreatment population: 5 male, 5 women ages:19-35 (mean AUC_i)/(mean AUC) = 55.4/11.5 description: A fixed-order study was conducted in 10 healthy volunteers with a 2-week washout period between the phases. In one arm of the study, a single 20-mg dose of simvastatin was administered orally; the second arm entailed administration of a single 20-mg dose of simvastatin orally after 2 weeks of treatment with 120 mg diltiazem twice a day. RESULTS: Diltiazem significantly increased the mean peak serum concentration of simvastatin by 3.6-fold (P < .05) and simvastatin acid by 3.7-fold (P < .05). Diltiazem also significantly increased the area under the serum concentration-time curve of simvastatin 5-fold (P < .05) and the elimination half-life 2.3-fold (P < .05). None None NOTE: The AUC_i/AUC value given is the AUC_0-24. route of administration: oral study duration: 14 days population: 12 healthy volunteers (all male), not heavy smokers (&lt;10 cigarettes/day). tested for known CYP450 polymorphisms? NO ages: 18-45 description: SUBJECTS: Twelve healthy male volunteers aged 18-45 years participated in this study. They were extensively screened within 3 weeks of study entry and had to be medically and mentally healthy, as evidenced by medical history, full physical examination, routine clinical laboratory investigations and electrocardiograms (ECGs). Their body-mass index had to be within the range 19 +/- 29 kg/m2, and they were not allowed to be heavy smokers (less than ten cigarettes or equivalent per day). On admission to the unit, they were screened for alcohol or drug use. No concomitant medication was allowed, with the exception of paracetamol for severe (head)aches. METHODS: Twelve male subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups in this two-period crossover study, with a medication-free washout interval of at least 2 weeks. For each study period, they were admitted to the clinical pharmacology institute 1 day before the start of the study. After admission, subjects were re-screened for alcohol and drugs. During one treatment period, subjects were given cimetidine (800 mg b.i.d. orally) for 14 days, with mirtazapine (30 mg nocte orally) added from the 6th to the 12th day of this period. During the alternate treatment period, cimetidine tablets were replaced by placebo tablets. Medication was taken together with water. Standard meals and snacks were served at fixed times of day. The use of alcohol was forbidden for 48 h prior to the start of the study and up to 48 h after the last study day. There were restrictions with regard to the use of coffee, tea and chocolate. The daily dosages of mirtazapine (30 mg nocte) and cimetidine (800 mg b.i.d.) were in agreement with the manufacturers' recommendations and coincided with current therapeutic practice. RESULTS: The combined administration of mirtazapine and cimetidine resulted in a statistically significant increase in AUC_0-24 of mirtazapine compared with the administration of mirtazapine as a single drug (AUC_0-24: 979 versus 635 ng x h/ml). None None NOTE: The AUC_i/AUC value is the AUC_0-inf of the oral dose of duloxetine. The object drug's dose given is the oral dose. route of administration: oral (both duloxetine and fluvoxamine), and IV (duloxetine) study duration: 24 days population: 14 healthy smokers (all male) tested for known CYP450 polymorphisms? No ages: 18-65 description: Healthy subjects were selected by the investigators based on their medical history, physical examination, ECGs and routine clinical laboratory test results. Up to 18 male smokers (aged 18–65 years) were to be enrolled in the fluvoxamine study. Sixteen men who were smokers were enrolled, and 14 completed the study. Two subjects were withdrawn by the investigator before receiving the study drug. The mean (+/- SD) age of the subjects was 37 +/- 11 years, the mean height was 174 +/- 6 cm, the mean bodyweight was 76.9 +/- 10.6 kg and the mean body mass index (BMI) was 25.4 +/- 2.9 kg/m2. The majority of subjects were Caucasian (81%) and the rest were African American. METHODS: This was an open-label, four-period, sequential crossover study. The dosing sequence started with duloxetine administration only (intravenous or oral; dosing periods 1 and 2), followed by duloxetine (intravenous or oral) in the presence of steady-state fluvoxamine (dosing periods 3 and 4). Duloxetine administration was planned on days 1, 5, 14 and 20 and fluvoxamine was administered from days 8 to 24. The sequence of intravenous and oral duloxetine dosing was randomized. The oral dose of duloxetine was a single 60-mg dose and the intravenous dose of duloxetine was a 10-mg infusion over 30 minutes. Fluvoxamine was initiated at a single dose of 50 mg for 1 day followed by 100 mg once daily for at least 16 additional days. Subjects unable to tolerate fluvoxamine 100 mg once daily were discontinued from the study. The washout period between each dose of duloxetine was a minimum of 4 days and a maximum of 14 days. RESULTS: The oral duloxetine C_max and AUC_inf were increased by 141% (90% CI 93, 200) and 460% (90% CI 359, 584), respectively, whereas the intravenous duloxetine AUC_inf increased by 170% (90% CI 121, 230). None None None None When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n = 14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t_1/2 was increased approximately 3-fold. NOTE: The AUC_i/AUC is from the AUC_0-inf of all the subjects taken together, not separated by genotype. route of administration: oral study duration: 4 days population: 12 healthy volunteers (all male), all nonsmokers tested for known CYP450 polymorphisms? Yes -- CYP2D6 genotypes - 8 EMs, 1 PM, 3 UMs ages: 20-29 description: 12 male volunteers (age range: 20–29 years; weight range: 65–89 kg) were recruited. The subjects were ascertained to be in good health by medical history, physical examination, and standard hematological and clinical chemistry tests. All subjects were non-smokers and used no concomitant medications. All 12 subjects completed the study according to the protocol. Genotyping of CYP2D6 revealed that eight subjects could be classified as EMs: six of them were homozygous for CYP2D6*1 allele, and two of them had the genotype CYP2D6*1/*4. One subject was classified as PM having the CYP2D6*3/*4 genotype, and three subjects without *3 or *4 were classified as UMs having a CYP2D6*1/*1x2 genotype. This high frequency of UM (25%) was much more than expected, but the subjects were not selected for the study by genotype. METHODS: The study was an open-label, randomized, three-phase crossover study with a washout period of 4 weeks between the phases. The volunteers were given either no pretreatment (control phase) or oral terbinafine (terbinafine phase) for 4 days in a randomized order. The dose of terbinafine (Lamisil 250mg tablet; Novartis Pharma, Huningue, France) was 250mg once a day at 0800 hours for 4 days. Terbinafine were self-administered by subjects except for the last doses, which were administered by the study personnel. One hour after the last dose of terbinafine was ingested, all volunteers received 75 mg oral dose of venlafaxine (Efexor 75 mg tablet; Wyeth Pharmaceuticals, New Lane, Havant, Hants, England) at 0900 hours with 150 ml of water. During all phases, the subjects fasted overnight before administration of venlafaxine and continued fasting until a standardized lunch was served 4 h after venlafaxine ingestion. The subjects were forbidden to use any other medication for 14 days before and during the study and any drug known to cause enzyme induction or inhibition for a period of 30 days before the study. Caffeine, grapefruit juice, and alcohol-containing beverages were not allowed during the study. RESULTS: When all the subjects were examined together, without subdivision into groups according to the genotype, terbinafine pretreatment increased the area under the plasma concentration–time curve (AUC_0–inf) of venlafaxine 4.9-fold (range: 1.5- to 8.2-fold; P&lt;0.001). None None NOTE: The AUC_i/AUC value given is the AUC_0-inf taken from Table 1. route of administration: oral study duration: 6 days population: 12 healthy Japanese volunteers (9 male, 3 female) tested for known CYP450 polymorphisms? Yes -- CYP2D6 genotypes - 4 with no mutated allele, 6 with one mutated allele, 2 with 2 mutated alleles ages: 20-35 description: SUBJECTS: Twelve healthy Japanese volunteers (nine males, three females) were enrolled in this study. Their mean +/- SD of age (range) was 24.8 +/- 2.5 (20–35) years and mean body weight was 58.3 +/- 8.5 (46–75) kg. The subjects had the following CYP2D6 genotypes: wt/wt (4 subjects), *10/wt (6), *10/*10 (1) and *5/*10 (1), respectively. No subjects regarded as poor metabolizers were included. These patients were divided into three groups according to the number of mutated alleles: no mutated allele in 4, one mutated allele in 6 and two mutated alleles in 2 subjects. METHODS: A randomized crossover study design was conducted at intervals of 4 weeks. One capsule containing either 125 mg of terbinafine or a matched placebo with 240 ml of tap water was given once daily at 0800 hours for 6 days. Compliance of the test drug was confirmed by pill-count. RESULTS: The AUC (0–48) of paroxetine during trebinafine treatment was higher than placebo by 2.53-fold (1.85, 4.58-fold). The total AUC of paroxetine during trebinafine treatment was higher than placebo by 2.88-fold (1.99, 5.41-fold). None None None None Route of administration: oral (inferred because IV formulations do not appear to be available for sertraline and desipramine) study duration: see below population: 9 healthy males; all extensive metabolizers of dextromethorphan (o-demethylation) ages: mean(std dev): &quot;adults&quot; but no mention of age. It can be inferred that these were healthy male adults and not exclusively elderly or children Description: The pharmacokinetic interactions of sertraline and fluoxetine with the tricyclic antidepressant desipramine were studied in 18 healthy male volunteers phenotyped as extensive metabolizers of dextromethorphan. Concentrations in plasma were determined after 7 days of desipramine (50 mg/day) dosing alone, during the 21 days of desipramine and selective serotonin reuptake inhibitor (SSRI) coadministration (fluoxetine, 20 mg/day; sertraline, 50 mg/day), and for 21 days of continued desipramine administration after SSRI discontinuation. Desipramine Cmax was increased 4.0-fold versus 31% and AUC0-24 was increased 4.8-fold versus 23% for fluoxetine versus sertraline, respectively, relative to baseline after 3 weeks of coadministration. Desipramine trough concentrations approached baseline within 1 week of sertraline discontinuation but remained elevated for the 3-week follow-up period after fluoxetine discontinuation. Concentrations of SSRIs and their metabolites correlated significantly with desipramine concentration changes (for fluoxetine/norfluoxetine, r = 0.94 to 0.96; p &lt; 0.001; for sertraline/desmethylsertraline, r = 0.63; p &lt; 0.01). Thus, sertraline had less pharmacokinetic interaction with desipramine than did fluoxetine at their respective, minimum, usually effective doses. Route of administration: oral (inferred because IV formulations do not appear to be available for sertraline and desipramine) study duration: see below population: 17 volunteers (design called for 24 but several dropped out or were excluded due to non-compliance); all participants were extensive metabolizers of dextromethorphan (o-demethylation) ages: mean(std dev): 30.4 (+/-5.2) AUC_i/AUC (24 hour): 838 / 611 = 1.37 NOTE: AUC increase mentioned is for the phase of the study using 50mg of paroxetine. Description: The pharmacokinetics of desipramine when coadministered with the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline were studied in 24 healthy male volunteers (CYP2D6 extensive metabolizers). Desipramine (50 mg/day) was administered for 23 days in each phase of the crossover study with a 7-day drug-free period between phases. In addition, subjects were randomly assigned to receive concomitant paroxetine (20 mg/day on days 8 through 17 followed by 30 mg/day on days 18 through 20) or sertraline (50 mg/day on days 8 through 17 and 100 mg/day on days 18 through 20). SSRI treatments were switched between phases. After 10 days of coadministration at the lower dose, mean desipramine maximum concentration in plasma (Cmax) relative to baseline increased from 37.8 to 173 ng/mL (+358%) with paroxetine versus from 36.1 to 51.9 ng/mL (+44%) with sertraline; the mean desipramine 24-hour area under the concentration-time curve (AUC[24]) increased from 634 to 3,305 ng x h/mL (+421%) with paroxetine versus from 611 to 838 ng x h/mL (+37%) with sertraline; and the mean desipramine trough value (C0) increased from 18.5 to 113 ng/mL (+511%) with paroxetine versus from 18.3 to 21.8 ng/mL (+19%) with sertraline (all increases, p &lt; 0.001). An approximately 10-fold increase in the Cmax and AUC(24) of paroxetine and an approximately 2-fold increase in these parameters for sertraline occurred simultaneously with the desipramine concentration changes. Thus, when coadministered with 50 mg/day desipramine, sertraline had significantly less pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively. None None Route of administration: oral study duration: PK values of a single dose of desipramine was compared with the same values after eight days of treatment with desipramine + sertraline population: 6 healthy males, all participants were extensive metabolizers of dextromethorphan (o-demethylation) (c.f. page 154, paragraph 3). ages: mean(std dev):42 (9) AUC_i/AUC (24 hour): 796/516 = 1.54 Description: Participants received a 50 mg single dose of either desipramine or imipramine under three conditions: alone, after a single 150 mg dose of sertraline, and after the eighth daily 150 mg dose of sertraline. Plasma samples were analyzed for desipramine or imipramine concentration by HPLC with electrochemical detection, and pharmacokinetics were determined with use of noncompartmental analysis of individual data. RESULTS: Multiple-dose, but not single-dose, treatment with sertraline significantly reduced apparent plasma clearance (CL/F) and prolonged the half-life of desipramine relative to baseline. These changes resulted in higher plasma desipramine concentrations, as indicated by a significant increase in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] (22% and 54%, respectively). Both single- and multiple-dose treatment with sertraline significantly reduced the CL/F of imipramine. This effect was stronger after multiple predoses of sertraline, when imipramine Cmax and AUC(0-infinity) were increased by 39% and 68%, respectively. These treatment effects were consistent between individuals. None None NOTE: The AUC_i/AUC value given is the AUC_0-inf calculated from Table 1. route of administration: oral study duration: 8 days population: 6 healthy Japanese volunteers (all male); 3 smokers, 3 nonsmokers tested for known CYP450 polymorphisms? NO ages: 26-36 description: SUBJECTS: Six healthy male Japanese volunteers who had given informed consent participated in this study. Their mean age and body weight were 31 +/- 4 years (range, 26-36 years) and 66.3 +/- 5.1 kg (range, 57-72 kg), respectively. Three subjects were nonsmokers and three were smokers (20-40 cigarettes per day). All subjects were in good health as assessed by medical history, physical examination, routine hematology, blood chemistry, urinary tests, and cardiac function (electrocardiography). STUDY DESIGN: A randomized crossover design with two phases was used. A 7-day washout period separated the two treatment conditions. Each subject received an oral dose of mexiletine (200 mg) at 7:00 AM with 100 mL of water. In the one phase, they received mexiletine alone (study 1); in the other phase, they received fluvoxamine (50 mg twice a day) for 7 days, and on the eighth day they received mexiletine and fluvoxamine concomitantly at 7:00 AM (study 2). Each subject fasted overnight for at least 10 hours before the administration of mexiletine at 7:00 AM and continued to fast for an additional 6 hours after administration. The subjects were instructed not to take any medications or drink anything that included caffeine or alcoholic beverages for 1 week before the study and throughout the study. RESULTS: The area under the concentration-time curve and serum peak concentration of mexiletine in study 2 were significantly increased compared with those in study 1 (10.4 +/- 4.85 versus 6.70 +/- 3.21 µg x h/mL, P = .006 and 0.623 +/- 0.133 versus 0.536 +/- 0.164 µg/mL, P = .008, respectively). None None NOTE; The precipitant drug dose is the Period 3 dose of the EMs. The AUC_i/AUC is the combined (both EMs and PMs) AUC_0-8h of Period 3. route of administration: oral study duration: Period 1 - 3 days, Periods 2 and 3 - 7 days population: 10 healthy volunteers, all Caucasian, all nonsmokers tested for known CYP450 polymorphisms? Yes -- CYP2D6 phenotyping - 5 extensive metabolizers, 5 poor metabolizers ages: 22-45 description: SUBJECTS: Twelve healthy white subjects, 6 men and 6 women, aged 22 to 45 years (mean, 30 years) and weighing 56 to 94 kg (mean, 81 kg for the men and 69 kg for the women), participated in this study, which included 7 EMs and 5 PMs of debrisoquin. The debrisoquin metabolic ratio (MR) ranged from 0.57 to 2.2 in EMs and from 35 to 260 in PMs. Genotyping of CYP2D6 and CYP2C19 was performed in 1 subject (subject No. 12) by the methods of Heim and Meyer (CYP2D6*3 and *4) and de Morais et al (CYP2C19*2). All subjects were healthy as assessed by medical history, physical examination, urine drug screen, standard 12-lead electrocardiogram, virologic testing, and routine laboratory analyses. All were nonsmokers and had been drug-free for at least 1 week before the study. Two EM subjects (subjects No. 1 and No. 4) were not able to participate in period 3 because of travel abroad and, therefore, were replaced by 2 new EMs (subjects No. 12 and No. 13). They also followed the protocol in period 1 before entering period 3. METHODS: Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively. Initially, a single oral dose of fluvoxamine (25 mg to PMs and 50 mg to EMs) was given [Period 1], followed by 1 week of daily administration of 25 mg × 2 to EMs and 25 mg × 1 to PMs [Period 2]. Caffeine (day 6) and omeprazole (day 7) were again administered at the steady state of fluvoxamine. Later the study protocol was repeated with a lower dose of fluvoxamine, 10 mg × 2 to EMs and 10 mg × 1 to PMs for 1 week [Period 3]. Concentrations of fluvoxamine, caffeine, omeprazole, and their metabolites were analyzed by HPLC methods in plasma and urine. Because fluvoxamine kinetics is partly dependent on the polymorphic enzyme CYP2D6, we gave double the dose of fluvoxamine to EMs of debrisoquin compared with PMs of debrisoquin to obtain similar plasma concentrations of fluvoxamine. RESULTS: The geometric means of omeprazole AUC(0-8 h) increased with 174% (P &lt; .001) with 10 mg x 1 or x 2 [Period 3] and 330% (P &lt; .001) with 25 mg x 1 or × 2 of fluvoxamine [Periods 1-2]. None None None None Quote: &quot; Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p &lt; 0.001) and reduced clearance of intravenously administered midazolam by 54% (p &lt; 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p &lt; 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.&quot; None None Quote: &quot; The effect of erythromycin on the pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase, was investigated in 12 healthy volunteers. Each subject received a single 10 mg dose of atorvastatin on two separate occasions, separated by 2 weeks. Erythromycin (500 mg qid) was given from 7 days before through 4 days after the second atorvastatin dose. Atorvastatin concentrations were determined by an enzyme inhibition assay, which measured both atorvastatin and active metabolites. When erythromycin was coadministered with atorvastatin, mean Cmax and AUC(0-infinity) increased by 37.7% and 32.5%, respectively. Mean terminal half-life was similar following each atorvastatin dose. Possible mechanisms for this interaction include erythromycin inhibition of first-pass conversion of atorvastatin to inactive metabolites and erythromycin inhibition of P-glycoprotein-mediated intestinal or biliary secretion.&quot; NOTE: The AUC_i/AUC is from the heterozygous EMs and calculated from Table 1. route of administration: oral study duration: 6 days population: 18 healthy volunteers (9 male, 9 female), all Japanese tested for known CYP450 polymorphisms? Yes -- CYP2C19 genotypes - 6 homozygous EMs, 6 heterozygous EMs, 6 homozygous PMs ages: mean 25.1 years (+/- 3.8) description: Eighteen healthy Japanese volunteers (9 men and 9 women) who were H. pylori-negative were enrolled in this study. Their mean age was 25.1 +/- 3.8 years and mean body weight was 56.6 +/- 13.3 kg. Most subjects in this study had participated in our previous studies. The mutated alleles for CYP2C19, CYP2C19*3(*3), and CYP2C19*2(*2) had been identified using polymerase chain reaction-restriction fragment length polymorphism methods of De Morais et al, before this study. The CYP2C19 genotype analyses revealed 5 different patterns as follows: *1/*1 in 6, *1/*2 in 3, *1/*3 in 3, *2/*2 in 5, and *2/*3 in 1. These were divided into 3 groups, homozygous EMs (*1/*1, n=6), heterozygous EMs (*1/*2 and *1/*3, n=6), and PMs (*2/*2 and *2/*3, n=6). METHODS: A randomized double-blind placebo-controlled crossover study design in 3 phases was conducted at intervals of 2 weeks. Clarithromycin (400 mg) as a capsule containing the equivalent of 2 tablets, fluvoxamine (25 mg) as a capsule containing the equivalent of a tablet, or matched placebo was given orally twice a day (9 AM, 9 PM) for 6 days. Six volunteers within each group were allocated to each of the 3 different drug sequences: placebo-clarithromycin-fluvoxamine, fluvoxamine-placebo-clarithromycin, or clarithromycin-fluvoxamine-placebo. On day 6, they took a single oral 60-mg dose of lansoprazole with 400 mg dose of clarithromycin, 25mg dose of fluvoxamine, or placebo after overnight fasting (9 AM). No other medications were taken during the study periods. No meal was allowed until 4 hours after the dosing (1 PM). The use of alcohol, tea, coffee, and cola was forbidden during the test days. RESULTS: Clarithromycin treatment significantly increased Cmax and AUC_0-24 of lansoprazole in heterozygous EMs (P&lt;0.05) and in PMs (P&lt;0.01), and prolonged elimination half-life by 1.6-fold (P&lt;0.05) in PMs. Calculated from Table 1, the AUC_i/AUC were: 1.62 (homozygous EMs), 1.71 (heterozygous EMs [p&lt;0.05]), and 1.89 (PMs [p&lt;0.01]). None None route of administration: oral study duration: 16 days population: 9 nonsmoking, stable schizophrenic patients, physically healthy (all male) tested for known CYP450 polymorphisms? YES -- CYP2D6 phenotyping - all extensive metabolizers ages: mean age 38.0 +/- 12.4 description: SUBJECTS:Nine non-smoking stable schizophrenic patients (mean age 38.0 +/- 12.4 years and weight 59.1 +/- 12.3 kg) gave informed consent to participated in this study. Each patient met the DSM-IV criteria for schizophrenia, had not previously received CLZ or FLV and had not consumed beverages containing caffeine, alcohol or grapefruit juice for at least 1 month prior to the study. Patients were also not taking any known CYP1A2 inducers or inhibitors or other routinely prescribed medications. Only lorazepam “as needed” 2 mg every 4–6 h was allowed during the study. All patients were evaluated to be physically healthy by physical examination, medical history, and routine hematological, biochemical and urinalysis tests. These patients were not classified as refractory schizophrenics by the criteria proposed by Kane et al. (1988). Prior to the study, these patients were phenotyped with dextromethorphan and all subjects were extensive metabolizers of CYP2D6 (Lane et al. 1996). Also, prior to the study, these patients were also administered a test dose of caffeine 200 mg and CYP1A2 status was evaluated. Caffeine and metabolite ratios were within values previously reported by other investigators, indicating the absence of any unusual metabolizers of CYP1A2 in this group of patients (Bertilsson et al. 1994). METHODS: On the first study day at 8:00 a.m., each patient received a single CLZ 50 mg dose (two 25 mg tablets). Venous blood samples (5 ml) were collected in heparinized tubes and obtained prior to the dosage administration and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36 and 48 h post-drug. The blood samples were centrifuged at 3000 rpm for 15 min and the separated plasma frozen at 920°C until assay. FLV 50 mg was administered twice a day to each patient from day 3 to day 16. On day 15, CLZ 50 mg was given as a single dose. Blood samples were obtained at the same times during the first study period. RESULTS: The total AUC of CLZ increased by a factor of 2.84 upon FLV addition (t = 5.364, P = 0.0007). None None &quot;The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady state concentration was evaluated in 10 male in-patients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased three-fold following co-administration of fluvoxamine. Fluvoxamine and thioridazine should not be co-administered.&quot; None None NOTE: The AUCi/AUC value is calculated from Table 1. route of administration: oral study duration: 2 days population: 10 healthy, nonsmoking volunteers (6 male, 4 female); 7 Caucasian, 2 African-American, 1 Hispanic tested for known CYP450 polymorphisms? No. ages: 21-47 description: Ten healthy, nonsmoking volunteers (6 male and 4 female), aged 21–47 years, initiated participation after giving written informed consent. All were active, ambulatory adults, with no evidence of medical disease and taking no other medication. The ethnic distribution was: 7 Caucasian, 2 African-American, 1 Hispanic. METHODS: The study was a randomized, double blind, 5-way crossover study with at least 7 days elapsing between trials. Medications were: trazodone hydrochloride, 50 mg (Desyrel; Bristol-Myers Squibb, Princeton, NJ); zolpidem tartrate, 5 mg (Ambien; Sanofi-Aventis, Bridgewater, NJ); and clarithromycin, 500 mg (Biaxin; Abbott, North Chicago, IL). The five treatment conditions were: (i) placebo + placebo, (ii) zolpidem + placebo, (iii) zolpidem + clarithromycin, (iv) trazodone + placebo, and (v) trazodone + clarithromycin. All medications were identically packaged in opaque capsules (void space filled with sucrose) and administered orally. Subjects were given 500 mg doses of clarithromycin (or matching placebo) at approximately 24 h, 8 h, and 1 h prior to, and again at 8 h after, administration of zolpidem, trazodone, or placebo. At 7 am on the study day, subjects were admitted to the Clinical Psychopharmacology Research Unit at Tufts University School of Medicine. They ingested a light breakfast with no caffeine containing beverages or food, and no grapefruit juice. The 500 mg dose of clarithromycin (or matching placebo) was administered with 200 ml of tap water. One hour later, subjects took a “challenge” dose of 5 mg zolpidem, 50 mg of trazodone, or placebo with 200 ml tap water. Volunteers resumed a normal diet at noon (without caffeine). Venous blood samples were drawn into heparinized tubes prior to challenge dosing and at postdosage times of 1/2, 1, 1 1/2, 2, 2 1/2, 3, 4, 5, 6, and 8 h. Another 500 mg of clarithromycin or placebo was given following the 8-h blood sample. The subjects were then discharged from the study unit. They returned the next morning for a 24-h blood sample. All blood samples were centrifuged, and the plasma was separated and frozen until the time of the assay. RESULTS: Coadministration of trazodone with clarithromycin compared to placebo significantly increased peak plasma concentration (C_max) (681 ng/ml vs. 922 ng/ml), prolonged t_1/2 (7.1 h vs. 13.9 h), increased AUC (4,668 ng/ml x h vs. 9,275 ng/ml x h), and reduced oral clearance (166 ml/min vs. 89 ml/min). None None Route of administration: oral study duration: 14 healthy male volunteers received itraconazole, 200 mg, or placebo once daily for 5 days; on day 4, 80 mg of rosuvastatin was coadministered. population: 14 male ages: 18-65 AUC_i/AUC (geometric least-square mean, 0 to the time of last quantifiable concentration): 1.28 None None Route of administration: oral polymorphic enzyme: no study duration: three days pre-treatment with itraconazola @ 200mg with a single oral dose of alprazolam on day 4 @ 0.8mg and two days continued dosing with itraconazole population: 10 male ages: 25-38 description: From Table 1, the AUC_i/AUC increase from 0-time of measurement: 357/221 = 1.615; AUC_i/AUC increase from 0-inf: 671/252 = 2.66 None None Route of administration: oral polymorphic enzyme: NO study duration: 7 days pravastatin only, 8 days pravastatin and clarithromycin dose: .040g pravastatin 1xday .5g clarithromycin 2xday population: 45 men and women (only 15 received pravastatin) ages:18-60 (mean AUC_i)/(mean AUC) = 114/54 description: Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). None None None None Quote: Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. NOTE: The AUC_i/AUC value given is the AUC_0-24 and calculated from Table II. route of administration: oral study duration: 10 days population: 18 healthy volunteers (9 male, 9 female) tested for known CYP450 polymorphisms? NO ages: 18-41 description: SUBJECTS: Twenty-four healthy volunteers were enrolled and 18 (9 men and 9 women) completed the study. The subjects ranged in age from 18 to 41 years (mean 26 years). Weight ranged from 43 to 71 kg (mean 56 kg) for the women and 60 to 83 kg (mean 71 kg) for the men (Table I). Health status was established on the basis of medical history, physical examination, and biochemical laboratory test findings. Subjects were excluded from entry into the study if these test results were outside the normal ranges and if there was a history of drug or alcohol abuse. Additional exclusion criteria included: sensitivity to antidepressants or cimetidine; ingestion within the prior 3 months of agents that might alter hepatic enzyme activity; ingestion of any prescription or investigational drug within one month and any nonprescription drug within 2 weeks before the study; excessive tobacco smoking (more than 10 cigarettes/day) or caffeine ingestion (more than 5 cups of coffee/day). Of the original 24 volunteers, six did not complete the study. One withdrew from the study for personal reasons unrelated to the drug, and one other participant was dropped from the study because of an infection noticed on day 5, also unrelated to the study drug. Four volunteers withdrew because of apparent drug-related events on days 1 to 3. The symptoms leading to discontinuation included one or more of the following: nausea, vomiting, dizziness, blurred vision, mydriasis, nervousness, tremor, abdominal pain, and headache. The remaining 18 volunteers completed the study. METHODS: The study was conducted according to an open-label, nonrandomized, cross-over design and lasted 11 days. The study was divided into two 5-day periods during which the participants resided in a clinical unit, with the exception of a single night in between the two 5-day periods that was spent outside the clinic. The subjects began their stay on the night before the first experimental day. At 8:00 AM of the following morning (day 1), each participant ate a standard, medium fat breakfast consisting of cereal, low-fat milk, one egg, one piece of bacon, one piece of toast with butter, and one glass of orange juice. Thirty minutes later, the participants ingested a single 25-mg tablet of venlafaxine. A multiple oral dose regimen began after this first dose; each participant ingested a single 50-mg tablet of venlafaxine with 8 ounces of water every 8 hours for the next 10 days. The control period (i.e., no cimetidine) lasted from day 1 through day 5. Subjects fasted overnight before the morning dose on days 5 and 10. The experimental drug interaction phase of the study began on the evening of day 6, when each subject ingested a single 800-mg tablet of cimetidine at 10:00 PM with 8 ounces of water. Venlafaxine dose administration continued during this phase of the study as described above. Once daily cimetidine administration (800 mg/day) continued through day 10, and participants were discharged from the clinical unit on day 11. RESULTS: Consistent with the above findings, cimetidine produced a significant increase in the C_max, C_min, and AUC of venlafaxine (P &lt; 0.001) but no significant changes in these three parameters for 0-des-methylvenlafaxine. None None NOTE: This is entered as &quot;for&quot; but the evidence board suggests that the AUC value might not be significant. route of administration: oral study duration: 21 days population: 17 healthy subjects (96% male), 64% white tested for known CYP450 polymorphisms? NO ages: 19-44 description: Studies 1 and 2 enrolled healthy male and female subjects aged 18-45 years with a body mass index (BMI) of 18-33 kg/m2 between August and September 2006 (Study 1) or August and November 2006 (Study 2). Excluded were women who were pregnant, breastfeeding or of childbearing potential without an acceptable contraceptive method; subjects with any significant acute or chronic medical or psychiatric illness or history of neuroleptic malignant syndrome, serotonin syndrome or acute dystonic reactions and subjects with a history of allergy to the study treatments or related compounds, or exposure to monoamine oxidase inhibitors, or CYP2D6 or CYP3A4 inhibitors or inducers in the 4 weeks before the study. The majority of subjects in Study 2 were male (96%), and 64% were white. The mean +/- SD age was 29 +/- 8 years (range 19-44 years), the mean +/- SD weight was 79.5 +/- 8.7 kg (range 60.2-98.6 kg) and the mean +/- SD BMI was 25.3 +/- 2.6 kg/m2 (range 21.6-32.0 kg/m2). Of the subjects who received concomitant medications while taking aripiprazole and venlafaxine, eight received lorazepam for akathisia and five received benztropine for EPS-related AEs. Of the 25 subjects who received treatment (safety sample), 23 completed treatment with escitalopram monotherapy and received adjunctive aripiprazole. Two subjects discontinued escitalopram monotherapy (investigator’s decision, n = 1; consent withdrawn, n = 1). Six subjects discontinued during adjunctive aripiprazole treatment (AEs, n = 3; consent withdrawn, n = 3) and 17 subjects completed the study (pharmacokinetic sample). The design of Study 2 was similar, except that subjects received escitalopram 10 mg/day for 7 days (Day -7 to Day -1) before the addition of once-daily aripiprazole 10 mg/day on Study Day 1 for a further 14 days (Day +1 to Day +14). Mean steady-state plasma concentration–time profiles for escitalopram administered alone or in combination with aripiprazole were similar (Figure 1C) with a small effect of aripiprazole 10 mg/day on AUC_TAU (7% increase; Table 2). Based on the escitalopram C_min on Day 14 (at t = 0 h and t = 24 h), escitalopram plasma concentration appeared to be at steady state (Table 2). None None NOTE: The AUC_i/AUC value is calculated from Table 1 using the formula CL = dose / AUC route of administration: oral study duration: 5 days population: 6 young healthy volunteers (all male) tested for known CYP450 polymorphisms? YES -- CYP2D6 and CYP2C19 phenotyping - All extensive metabolizers ages: none given description: SUBJECTS: This was an open study of six young healthy male volunteers, all phenotyped as extensive metabolisers of sparteine (CYP2D6) (metabolic ratio &lt; 20) and mephenytoin (CYP2C19) (S/R ratio &lt; 0.5). All volunteers gave written informed consent. The study was approved by the regional ethics committee and the Danish National Board of Health. Before inclusion, all volunteers were screened by physical examination, laboratory tests and electrocardiogram. METHODS: On study day 1, the volunteers took a single oral dose of 250 mg tolbutamide (CYP2C9) (Tolbutamid ''Dak'', Nycomed DAK, Denmark) at 0800 hours. On study day 2, the volunteers took 100 mg sparteine (CYP2D6) (Depasan, Giulini Pharma, Germany), 100 mg mephenytoin (CYP2C19) (Mesantoin, Sandoz Pharmaceuticals, USA) and 200 mg caffeine (CYP1A2) (Koffein ''Dak'', Nycomed DAK) orally at 0800 hours. On study day 3, following an overnight fast from 2400 hours, the volunteers took a single oral dose of 200 mg quinidine sulfate (Kinidin ''Dak'', Nycomed DAK), equivalent to 511 umol quinidine. The volunteers were allowed normal meals after the blood sample at t = 1 h was drawn. Following a washout period of 6-8 weeks, the volunteers took 100 mg of fluvoxamine (Fevarin, Solvay Duphar, Netherlands) daily at 0800 hours on study days -1, 0, 1, 2, 3 and 4. The study procedures on days 1-4, above, were repeated. During the study, the volunteers refrained from intake of any other medications, alcohol or grapefruit juice. Consumption of coffee or xanthine-containing foods was not allowed for a period of 48 h before and the 12 h during caffeine testing. The quinidine and the quinidine and fluvoxamine sessions were performed without randomisation of the sequence, justified by only using hard end-points, i.e. drug- and metabolite-concentrations in plasma and urine, in the study. RESULTS: The total apparent oral clearance of quinidine was calculated as: CLq = Dose / AUCq (0 -&gt; inf). The quinidine total apparent oral clearance, clearance by N-oxidation and by 3-hydroxylation were statistically significantly reduced during fluvoxamine treatment by medians of 29%, 33% and 44%, respectively. See Table 1 and formula. None None Route of administration: oral study duration: two days pre-treatment with 200mg bid ketoconazole and a single treatment of 1mg alprazolam population: 17 male: 16 female: 1 ages: 22-55 NOTE: All participants were treated with alprazolam alone by only 4 participants received ketoconazole pre-treatment. AUC_i/AUC (0 to inf): 426.2/242.2 = 1.76 None None Route of administration: oral study duration: three days pre-treatment with ketoconazole oral 200mg bid; on day three a single 1mg dose of oral alprazolam; control group took placebo. population: 7 male, 0 female ages:21-44yrs AUC_I/AUC : 944/237 = 3.983 None None Route of administration: oral study duration: 13 days population: 18 participants; 5 male, 5 female ages:18-45 dose: 40mg of pravastatin on day one, three days no drug, days 6-10 participants were given 200mg itraconazole 1xday for 5 days, on day 10 a portion of the participants were given a single dose of 40 mg pravastatin. PK parameters were measured followed for another three days (mean AUC_i)/(mean AUC) = 75.2/50.6 (AUC is 0-infinity) description: n this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites. RESULTS: Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P &lt; .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P &lt; .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P &lt; .05). None None None None Quote: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske unders�er side effect rating scale. RESULTS: Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. None None Route of administration: oral polymorphic enzyme: NO study duration: 2 day pretreatment with erythromycin @ 500mg 3x/day NOTE: study states two day pretreatment but there were only four doses given before object drug was administered population: 12 male: 8 female: four ages:20-29 description: Table 2 shows AUC_i/AUC: 110/17.7 ng/ml*hr NOTE: The AUC_i/AUC value is from Table 1. route of administration: oral study duration: 8 days population: 15 healthy subjects (11 male, 4 female), all nonsmokers; 13 Caucasian, 1 Hispanic, 1 Asian tested for known CYP450 polymorphisms? NO ages: 23-40 description: SUBJECTS: Subjects were nonsmokers who were of normal build and had no clinically significant abnormalities. Fifteen subjects (4 females and 11 males) completed the study. Thirteen subjects were Caucasian, 3 were Hispanic, and one was Asian. Ages ranged from 23 to 40 years (mean = 32 +/- 5 years). At admission, mean height was 173 +/- 10 cm and mean weight was 71 +/- 13 kg. METHODS: The pharmacokinetics of 3 identical single therapeutic doses of olanzapine (5 mg) were determined in 15 healthy nonsmoking volunteers. The first dose of olanzapine was taken alone, the second given after a single oral dose of fluoxetine (60 mg), and the third given after 8 days of treatment with fluoxetine 60 mg, qd. There was an interval of 10 days between olanzapine doses of periods 1 and 2, and at least 15 days between olanzapine doses of periods 2 and 3. During each period, the volunteers remained in the clinical pharmacology unit for 24 hours following the administration of olanzapine. RESULTS: After single coadministration of fluoxetine, the C_max and AUC_0-inf of olanzapine increased by 18%, whereas the total apparent clearance decreased by 15%. None None Route of administration: oral study duration: four days pre-treatment with itraconazole (200mg 1x/day) and a single .25mg dose of oral triazolam on day 4 population: 9 : male: 3 female: 6 ages: 20-26 AUC_i/AUC (0 to infinity): 160/5.9 = 27 None None Route of administration: oral study duration: 5-phase randomized cross-over study with participants receiving a single oral dose of .25mg triazolam either simultaneously or 3,12, or 24 hours before triazolam population: 10 male: 6 female: 4 ages: 19-27 AUC_i/AUC 0 to infinity (itra simultaneous w/ TRZ): 38.2/12.3 = 3.1 AUC_i/AUC 0 to infinity (itra 3 hours prior to TRZ): 55.1/12.3 = 4.48 AUC_i/AUC 0 to infinity (itra 12 hours prior to TRZ): 53.2/12.3 = 4.33 AUC_i/AUC 0 to infinity (itra 24 hours prior to TRZ): 43.9/12.3 = 3.57 Average: 3.87 None None NOTE: The AUC_i/AUC value is calculated from Table 1 using equation 1. route of administration: oral study duration: 7 days population: 12 nonsmoking volunteers (all male) tested for known CYP450 polymorphisms? NO ages: 22-30 description: SUBJECTS: The study was carried out as an open, randomized, crossover study of 12 volunteers, all men with a median age of 23 years (range, 22-30 years). All were nonsmokers and had no known heart, liver, or kidney diseases according to clinical investigation, clinical chemical/hematological screening, and ECG test. They were not consuming alcohol or drugs on a regular basis at the time of the study. The volunteers consented to participate in the study on the basis of written and verbal information, and the study was approved by the regional ethics committee of the counties of Vejle and Funen and by the Danish National Board of Health. METHODS: The volunteers were randomized into three groups. All three groups went through three testing periods, which were separated by 2 weeks of washout. In all three periods, the volunteers abstained from ingesting methylxanthine-containing beverages, foods, and medication for 3 days before study and until the last blood sample was drawn. In period A, a blood sample was drawn before intake of a tablet of 300 mg theophylline ethylenediamine (Teofylamin; Nycomed DAK, Copenhagen, Denmark), containing 257 mg theophylline. In period B, the volunteers received a tablet of 50 mg fluvoxamine (Solvay Duphar BV, Weesp, the Netherlands) for 1 day, and during the following 6 days they received 100 mg fluvoxamine each day. On day 4, a blood sample was drawn before the intake of 300 mg theophylline ethylenediamine; thereafter, blood samples were drawn at 1, 2, 3, 4, 6, 8, 12, 24, 32, 48, 72, and 96 h. RESULTS: The total theophylline clearance was calculated as EQUATION 1 [Cl_13DMX = Dose / AUC_13DMX(total)] where Cl is clearance and AUC_13DMX(total) is the area under the plasma concentration time curve calculated by the trapezoidal rule with extrapolation from the last measurable concentration to infinity. Complete absorption of theophylline from the intestine was assumed. See Table 1 and equation 1. None None None None Route of administration: oral (inferred because IV formulations do not appear to be available for paroxetine and desipramine) study duration: see below population: 17 volunteers (design called for 24 but several dropped out or were excluded due to non-compliance); all participants were extensive metabolizers of dextromethorphan (o-demethylation) ages: mean(std dev): 30.4 (+/-5.2) AUC_i/AUC (24 hour): 3305 / 634 = 5.2 NOTE: AUC increase mentioned is for the phase of the study using 20mg of paroxetine. Description: The pharmacokinetics of desipramine when coadministered with the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline were studied in 24 healthy male volunteers (CYP2D6 extensive metabolizers). Desipramine (50 mg/day) was administered for 23 days in each phase of the crossover study with a 7-day drug-free period between phases. In addition, subjects were randomly assigned to receive concomitant paroxetine (20 mg/day on days 8 through 17 followed by 30 mg/day on days 18 through 20) or sertraline (50 mg/day on days 8 through 17 and 100 mg/day on days 18 through 20). SSRI treatments were switched between phases. After 10 days of coadministration at the lower dose, mean desipramine maximum concentration in plasma (Cmax) relative to baseline increased from 37.8 to 173 ng/mL (+358%) with paroxetine versus from 36.1 to 51.9 ng/mL (+44%) with sertraline; the mean desipramine 24-hour area under the concentration-time curve (AUC[24]) increased from 634 to 3,305 ng x h/mL (+421%) with paroxetine versus from 611 to 838 ng x h/mL (+37%) with sertraline; and the mean desipramine trough value (C0) increased from 18.5 to 113 ng/mL (+511%) with paroxetine versus from 18.3 to 21.8 ng/mL (+19%) with sertraline (all increases, p &lt; 0.001). An approximately 10-fold increase in the Cmax and AUC(24) of paroxetine and an approximately 2-fold increase in these parameters for sertraline occurred simultaneously with the desipramine concentration changes. Thus, when coadministered with 50 mg/day desipramine, sertraline had significantly less pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively. NOTE: The AUC_i/AUC was calculated from Table 2. The object_dose is the dose of imipramine given. route of administration: not sure, but likely oral study duration: 15 days population: 9 male inpatient veterans tested for known CYP450 polymorphisms? NO ages: 31-60 None None NOTE: The AUC_i/AUC value is calculated from Table 3 using the equation CL=dose/AUC, where CL is the total clearance, and is for all EMs. For PMs, the AUC_i/AUC is 0.83. route of administration: oral study duration: 11 days population: 17 male Dutch volunteers tested for known CYP450 polymorphisms? YES -- CYP2D6 phenotyping via sparteine - 9 EMs and 8 PMs ages: 20-24 None None NOTE: The AUC_i/AUC given is for EMs and calculated from Table 2 using the formula AUC = dose/Cl route of administration: oral study duration: 2 days population: 15 healthy men, all nonsmokers tested for known CYP450 polymorphisms? YES - CYP2D6 phenotyping -- 9 EMs (7 CYP2D6*1/*1, 2 CYP2D6*1/*4), 6 PMs (1 CYP2D6*3/*4, 4 CYP2D6*4/*4, 1 CYP2D6*7/*7) ages: average age 27 +/- 5 description: SUBJECTS: Fifteen healthy men (nine EMs and six PMs) participated in the study. Their mean (+/-SD) age was 27 +/- 4 years and 27 +/- 5 years, and their mean body weight was 71 +/- 8 kg and 84 +/- 11 kg for EMs and PMs, respectively (Table 1). All volunteers were nonsmokers and healthy as determined by routine physical examination, electrocardiogram, and laboratory tests. METHODS: Subjects received oral doses (N = 5) of 18.75 mg venlafaxine hydrochloride (Effexor, Wyeth-Ayerst Canada, Inc., Montreal, Canada) every 12 hours for 48 hours on two occasions: once alone and once during the concomitant administration of 50 mg of diphenhydramine hydrochloride (Benadryl, Warner Wellcome, Scarborough, Canada) every 12 hours. Diphenhydramine was also administered alone and during concomitant administration of venlafaxine. The three study arms were performed 1 week apart. Venlafaxine tablets were prepared by the Department of Pharmacy, Laval Hospital, by cutting 37.5-mg venlafaxine hydrochloride tablets in half. No other drugs, caffeine-containing foods or beverages, chocolate, or alcohol were allowed 48 hours before and during the study. RESULTS: When venlafaxine was administered alone, mean AUC0–12 values for all subjects studied were 3.1 +/- 2.2 umol.hr-1.L-1 in PMs and 0.8 +/- 0.6 umol.hr-1.L-1 in EMs, respectively ( p &amp;lt; 0.05). The right panels of Figure 2 illustrate plasma concentrations of venlafaxine measured after the oral administration of venlafaxine during concomitant administration of diphenhydramine in the same PM and EM. Coadministration of diphenhydramine did not alter the plasma concentrations of venlafaxine in the PM. In contrast, diphenhydramine increased the AUC0–12 of venlafaxine more than 4-fold in the EM, leading to values toward those measured in the PM subject. On average, diphenhydramine increased venlafaxine AUC0–12 by more than 2-fold in EMs ( p &amp;lt; 0.05). Figure 3 and Table 2 report the pharmacokinetic parameters observed in EMs and PMs on venlafaxine alone and during concomitant administration of diphenhydramine. The mean oral clearance of venlafaxine was more than 4-fold greater in EMs compared with PMs when venlafaxine was administered alone. In EMs, coadministration of diphenhydramine decreased oral clearance of venlafaxine by more than 2-fold ( p &amp;lt; 0.05), leading to values close to those measured in PMs. In contrast, coadministration of diphenhydramine did not affect the oral clearance of venlafaxine in PMs. None None NOTE: The AUC_i/AUC value is calculated from Table 1. route of administration: oral study duration: 12 days population: 19 Chinese patients diagnosed with schizophrenia or schizophreniform disorder (9 male, 10 female) tested for known CYP450 polymorphisms? NO ages: 18-45 description: SUBJECTS: Only the patients who were first-episode, had not obtained significant therapeutic effects or could not tolerate the side effects using clozapine, risperidone or any other antipsychotic drugs were enrolled in the study. In the study, 21 Chinese in-patients were involved; 2 subjects discontinued the study due to side effects of erythromycin on the digestive tract. Of the subjects who completed the study, 19 (10 females, 9 males; age 18–45 years, weight 41–60 kg) were diagnosed with schizophrenia or schizophreniform disorder (criteria of CCMD-III). They refrained from cigarettes and alcohol. METHODS: During the first period (days 1–8), multiple and rising doses of quetiapine were given to the subjects twice daily (b.i.d). The dosage started at 25 mg b.i.d, reached 200 mg b.i.d by day 4 and remained at 200 mg b.i.d on days 5–7. Only a morning dose of quetiapine (200 mg) was given on days 8. During the second period (days 9–12), fixed doses of quetiapine (200 mg, b.i.d) and erythromycin (500 mg, three times daily) were co-administered to the subjects. A final combination dose of quetiapine (200 mg) and erythromycin (500 mg) was given in the morning of days 12. RESULTS: For quetiapine, co-administration of quetiapine and erythromycin led to 68, 129 and 92% increases in mean C_max (P=0.001), AUC_0–inf (P=0.000) and t_1/2 (P=0.000), respectively, None None Route of administration: oral study duration: venlafaxine for 4 days followed by 14 days of venlafaxine and aripiprazole population: 27 (55% male) mean age (SD):35 (7) NOTE: aripiprazole dose was titrated over the 14 day period from 10mg/day to 20mg/day AUC_i/AUC: 657/777 = 1.183 (geometric means) Description: Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. ... In healthy subjects, point estimates [90% CI] for the ratios of geometric means of Cmax (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUCTAU (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. None None oute of administration: oral study duration: one day pretreatment w/ diltiazem 60mg 3x PO; on day two subjects continued diltiazem and received 1 dose of midazolam @ 15mg PO population: 9 female ages: 19-31 AUC_i/AUC 0 to infinity: 45 / 12 = 3.75 None None route of administration: oral study duration: 4 days population: 10 healthy volunteers; 4 men, 6 women ages: 20-22 description: The mean AUC(0-inf) of zolpidem was 34% larger (P = 0.09) during the itraconazole phase than during the placebo phase (Fig. 1, Table 1). The 95% CI for the mean ratio of zolpidem AUC(0-inf) after itraconazole and placebo was from 103% to 162%, indicating a statisti- cally signifcant effect of itraconazole. None None NOTE: AUC_i/AUC is AUC_0-24. route of administration: oral study duration: 6 days population: 12 healthy volunteers (all male), all Japanese tested for known CYP450 polymorphisms? No ages: 20-28 description: Twelve healthy Japanese male volunteers were enrolled in this study. Their mean age (+/- SD) was 24.0 +/- 2.0 years (range, 20-28 years), and their mean body weight was 64.8 +/- 6.2 kg (range, 53-86 kg). METHODS: A randomized crossover study design was conducted at intervals of 4 weeks. Two 40-mg tablets of verapamil (Vasolan; Eisai Pharmaceutical, Tokyo, Japan) 3 times daily (at 8 AM, 1 PM, and 6 PM) or matched placebo with 240 mL of tap water was given for 6 days. The volunteers took a single oral 1-mg dose of risperidone at 9 AM on day 6 with 240 mL of tap water. RESULTS: The total AUC of risperidone during verapamil treatment was higher than during placebo by 1.82-fold (95% CI, 1.24- to 2.82-fold). None None route of administration: oral study duration: Fluoxetine was dosed at 40 mg/day for 11 days. On the morning of the 12th day participants received a final dose of antidepressant followed by a 3-mCi dose of radio-labled erythromycin by IV then, 20 minutes later, a 2 mg dose of alprazolam orally. (See NOTE below) population: 16 healthy males, non-smokers, tested for known CYP450 polymorphisms? Yes; &quot;subjects were phenotyped with dextromethorphan prior to entering the study to exclude CYP2D6-poor metabolizers&quot; ages:18 - 25 description: Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism ( P &gt; 0.05). For nefazodone, a statistically significant inhibition was observed ( P &lt; 0.0005). Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration � versus � time curve (AUC; P &lt; 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P &lt; 0.05) compared with values at aseline. No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested. NOTE: Although erythromycin is known to inhibit CYP3A4 activity, it is the opinion of DIKB reviewer's, the dose of erythromycin given in this study was too low to have any relevant inhibitory effect on CYP3A4 None None None None Route of administration: oral polymorphic enzyme: NO study duration: both drugs were given once daily for 30 days; pharmacokinetic measures were taken on days 1 and 30 dose: 40mg pravastatin; 200mg itraconazole population: 104 ages:18-60 (mean AUC_i)/(mean AUC) = 210/188ng/ml/h description: There was no significant increase in the AUC of pravastatin Route of administration: oral study duration: volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of pravastatin (study II). population: 10 : 7 male, 3 female ages:19-29 RESULTS: In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p &lt; 0.05 and p = 0.063, respectively) by itraconazole. NOTE: a statistically significant increase in HMG-CoA inhibitors occured but we cannot distinguish which metabolites of pravastatin were increased from the study None None NOTE: The AUC_i/AUC value is calculated from Table II and is not statistically significant route of administration: oral study duration: 2 days population: 11 healthy volunteers, all nonsmokers tested for known CYP450 polymorphisms? NO ages: 20-40 description: SUBJECTS: Twelve healthy volunteers (8 men and 4 women), aged 20 to 40 years, participated after giving written informed consent. All were active ambulatory nonsmoking adults, with no evidence of medical disease and taking no other medications. Female subjects were not taking oral contraceptives and did not have contraceptive implants. One of the subjects did not ingest zolpidem as instructed during treatment; accordingly mean values for itraconazole treatment, n=11. METHODS: At 8 AM on study day 1, subjects entered the outpatient Clinical Psychopharmacology Research Unit where they received the initial dose of azole (or placebo) and remained under observation for 30 minutes. Subjects took a second dose of azole (or placebo) at home at 4 PM on day 1. On the morning of day 2, after ingesting a standardized light breakfast with no caffeine-containing food or beverages and no grapefruit juice, they returned to the Research Unit at approximately 7:30 AM. They fasted until 12 noon, after which they resumed a normal diet (without grapefruit juice or caffeine-containing food or beverages). The third dose of azole (or placebo) was given at 8 AM, and the single dose of zolpidem or placebo was given at 9 AM. A final azole (or placebo) dose was given at 5 PM. RESULTS: Coadministration of zolpidem with itraconazole reduced clearance (320 and 338 mL/min), but differences compared to the zolpidem plus placebo treatment did not reach significance. See Table II. None None None None Quote: Chemical Inhibition of CT and DCT Biotransformation in Microsomes. At 10micM R- or S-CT, ketoconazole reduced reaction velocity to 55 to 60% of control, quinidine to 80% of control, and omeprazole to 80 to 85% of control (Fig. 6). When the R- and S-CT concentration was increased to 100 M, the degree of inhibition by ketoconazole increased, while inhibition by quinidine decreased (Fig. 6). These findings are consistent with the data from heterologously expressed CYP isoforms. Route of administration: oral polymorphic enzyme: NO study duration: 4 days population: 7 male, 3 female ages:19-29 description: Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined. RESULTS: In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). None None Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of 3',5'-dihydrodiol, 3'-hydroxy, and 6'-exomethylene metabolites using a recombinant CYP3A4 system None None None None Route of administration: oral polymorphic enzyme: NO study duration: 7 days simvastatin only, 8 days simva and clarithromycin dose: .040g simvastatin 1xday .5g clarithromycin 2xday population: 45 men and women (15 received simvastatin) ages:18-60 (mean AUC_i)/(mean AUC) = 219/22 description: Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) Enzyme system: human liver microsomes NADPH added: yes inhibitor used: itraconazole reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: itraconazole effected a dramatic decrease in the formation of both metabolites from both lactone and acid forms of atorvastatin None None Enzyme system: recombinant human CYP3A5 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: According to the authors, this enzyme system catalyzed the above reactions similar to that of the CYP3A4 recombinant enzyme system whose Km values ranged from 1.4micM/L for atorvastatin lactone--&gt;para-hydroxy-atorvastatin to 29.7micM/L for the atorvastatin acid--&gt;ortho-hydroxy-atorvastatin None None Enzyme system: human liver microsomes NADPH added: yes inhibitor used: itraconazole reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: itraconazole effected a dramatic decrease in the formation of both metabolites from both lactone and acid forms of atorvastatin None None Enzyme system: recombinant human CYP3A4 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system catalyzed the above reactions with Km values ranging from 1.4micM/L for atorvastatin lactone--&gt;para-hydroxy-atorvastatin to 29.7micM/L for the atorvastatin acid--&gt;ortho-hydroxy-atorvastatin None None &quot;In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme&quot; None None &quot; Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%).&quot; None None &quot; Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%).&quot; None None None None Quote: Inhibition of metabolite formation by each inhibitor is summarized in Table 2. Ketoconazole (10micM) inhibited the formation of ziprasidone sulphoxide (sulphoxide and sulphone) by 79% and oxindole acetic acid N-dealkylated product) completely. Sulphaphenazole an furafylline did not inhibit the formation of ziprasidone sulphoxide. The formation of oxindole acetic acid was inhibited (~50%) by furafylline. The formation of ziprasidone metabolites was not inhibited by quinidine but rather increased. Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of both 1'-OH-triazolam and 4-OH-triazolam in a recombinant cyp3a4 Supersome system None None &quot;Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and alpha-hydroxyalprazolam.&quot; None None None None Quote: &quot;Co-incubation of human liver microsomes with the prototypic 3A4 inhibitor, troleandomycin, ( &gt; 50microM) resulted in no detectable formation of 1'-OH-alprazolam and 4-OH-alprazolam&quot; Route of administration: oral polymorphic enzyme: yes study duration: single dose with 72 hours of plasma level monitoring population: study does not state gender of participants ages: 22-30 description: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam. None None Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of both 1'-OH-triazolam and 4-OH-triazolam in a recombinant cyp3a5 Supersome system None None 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions (5.10)]. None None route of administration: oral study duration: &quot;In study 2, there were 2 study periods separated by a least 4 days. In period 1, subjects received 40 mg duloxetine every day for 5 days. Blood samples for the measurement of duloxetine plasma concentrations were taken immediately before duloxetine dosing on days 3 4, and 5 and at 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after dosing on day 5. In period 2, subjects received 20 mg paroxetine every day for 20 days Beginning on day 12 of this period, subjects again received duloxetine 40 mg every day for 5 days and samples were taken as in period 1, except that additional samples were taken 96 and 120 hours after the &amp;#64257;nal duloxetine dose. On the &amp;#64257;nal day of duloxetine dosing in each period, subjects fasted from midnigh until 4 hours after dosing. All doses of study drugs were supervised by study site personnel. &quot; population: 12 male; 11 of 12 were of Chinese or Malay decent NOTE: only 10 completed the study tested for known CYP450 polymorphisms? yes but exact genotype not mentioned only that all were genotypically CYP2D6 extensive metabolizers. ages: 21 - 27 description: &quot;Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold.&quot; None None None None Quote: Incubations of human liver microsomes with NEF and the CYP3A4 inhibitor ketoconazole resulted in a concentration-dependent inhibition of the formation of mCPP and OH-NEF (Fig. 3). None None Quote: Chemical Inhibition of CT and DCT Biotransformation in Microsomes. At 10micM R- or S-CT, ketoconazole reduced reaction velocity to 55 to 60% of control, quinidine to 80% of control, and omeprazole to 80 to 85% of control (Fig. 6). When the R- and S-CT concentration was increased to 100 M, the degree of inhibition by ketoconazole increased, while inhibition by quinidine decreased (Fig. 6). These findings are consistent with the data from heterologously expressed CYP isoforms. Drug-Drug Interactions: Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4). I None None &quot;Potent inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). When lovastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of lovastatin.&quot; None None Route of administration: oral study duration: 4 days pretreatment with 200mg oral itraconazole; a single, oral, 40mg dose of lovastatin on day 4 population: 12 male: 5 female: 7 (2 on contraceptive steroids) ages: 20-29 AUC_i/AUC: 546/15 = &gt;36.4 NOTE: AUC of lovastatin w/ placebo could not be measured but was known to be &lt; 15ng/ml*h None None Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None Drugs That Inhibit CYP3A4 (Ketoconazole) CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The AUC of eszopiclone was increased 2.2-fold by coadministration of ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days. Cmax and t1/2 were increased 1.4-fold and 1.3-fold, respectively. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. None None None None Quote: Chemical Inhibition of CT and DCT Biotransformation in Microsomes. At 10micM R- or S-CT, ketoconazole reduced reaction velocity to 55 to 60% of control, quinidine to 80% of control, and omeprazole to 80 to 85% of control (Fig. 6). When the R- and S-CT concentration was increased to 100 M, the degree of inhibition by ketoconazole increased, while inhibition by quinidine decreased (Fig. 6). These findings are consistent with the data from heterologously expressed CYP isoforms. None None Quote: &quot;Evaluation of BUP Hydroxylation by Individual cDNA-Expressed Human P450s. Because the biphasic kinetic data observed with low activity HLMs (HLMs 20 and 24) indicated the contribution of more than one enzyme to BUP hydroxylation at higher substrate concentrations, a panel of eight cDNA-expressed enzymes (SUPER- SOMES) was screened for BUP hydroxylase activity at 12 mM to identify enzymes requiring further investigation (Fig. 7). This sub- strate concentration was selected to ensure saturation of any high Km isozyme capable of catalyzing BUP hydroxylation. cDNA-expressed CYP2B6 demonstrated the highest rate of HBUP formation (7.0 pmol/min/pmol of P450). cDNA-expressed CYP2E1 and CYP3A4 catalyzed BUP hydroxylation at the second and third highest rates, although at 3- and 30-fold lower rates than cDNA-expressed CYP2B6 (2.4 and 0.23 pmol/min/pmol of P450, respectively). Of note, CYP2E1 was the only cDNA-expressed enzyme in which cytochrome b5 was coexpressed. Rates of BUP hydroxylation by CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP2D6 were greater than 30-fold lower than CYP2B6 (Fig. 7). HBUP formation in control microsomes was negligible.&quot; Metabolism and Excretion Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. None None Metabolism: Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups. None None Metabolism Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. None None None None Pharmacokinetic-related Interactions Clozapine is a substrate for many CYP 450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes. None None Quote: The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p&lt;0.01) and by 20% (p&lt;0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. None None Quote: To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved. METHODS: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction... Ketoconazole inhibition of N-dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N-dealkylation at therapeutically relevant concentrations.The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20-25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. None None Quote: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction. RESULTS: CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. Metabolism In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4 None None Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. None None None None Quote: Incubations of MIR with human liver microsomes resulted in the formation of OHM, DMM, and MIR-N- oxide (Fig. 1). Quinidine (5 micM) and alpha-naphthoflavone (0.5 micM),specific inhibitors of CYP2D6 and CYP1A2, respectively, partially inhibited MIR-hydroxylation. Ketoconazole (1 micM), a specific inhibitor of CYP3A4, inhibited MIR-N-demethylation and MIR-N-oxidation. NOTE: lowest MIR concentration tested was 25 micM None None Pharmacokinetic-related Interactions Clozapine is a substrate for many CYP 450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes. None None Quote: Ketconazole inhibited [clozapine] demethylation by 28+/-20% and 68+/-15% at 0.2 and 2 micM, respectively... CLZ-NO formation was inhibited by ketoconazole by 41+/-14% and 51+/-13% at 0.2 and 2 micM, respectively. Metabolism In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4 None None None None Quote: Chemical Inhibition of CT and DCT Biotransformation in Microsomes. At 10micM R- or S-CT, ketoconazole reduced reaction velocity to 55 to 60% of control, quinidine to 80% of control, and omeprazole to 80 to 85% of control (Fig. 6). When the R- and S-CT concentration was increased to 100 M, the degree of inhibition by ketoconazole increased, while inhibition by quinidine decreased (Fig. 6). These findings are consistent with the data from heterologously expressed CYP isoforms. 7.18 CYP3A4 and -2C19 Inhibitors In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance. None None None None Quote: Chemical Inhibition of CT and DCT Biotransformation in Microsomes. At 10micM R- or S-CT, ketoconazole reduced reaction velocity to 55 to 60% of control, quinidine to 80% of control, and omeprazole to 80 to 85% of control (Fig. 6). When the R- and S-CT concentration was increased to 100 M, the degree of inhibition by ketoconazole increased, while inhibition by quinidine decreased (Fig. 6). These findings are consistent with the data from heterologously expressed CYP isoforms. 7.6 Combined Administration with Clarithromycin Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.{See CLINICAL PHARMACOLOGY, Combined Administration with Antimicrobials (12.3)}. None None Metabolism: ... In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. None None None None Quote: The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers None None Quote: risperidone was incubated with human liver microsomes in the presence of different concentrations of inhibitors of CYP enzymes. Both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A) inhibited the formation of 9-hydroxyrisperidone in a concentration-dependent manner (Fig. 4). route of administration: oral study duration: single dose of 100 mg sertraline population: 12 healthy Chinese male, non-smokers tested for known CYP450 polymorphisms? Patients were genotyped for CYP2C19 polymorphisms and also phenotyped using the omeprazole/5-hydroxy-omeprazole metabolic ratio. 6 extensive metabolizers (EM) and 6 poor metabolizers (PM) were chosen using stratified random selection from a pool of 66 EMs and 11 PMs. ages: 19 - 22 years description: The poor metabolizers had a 41% increase in sertraline AUC(0-inf) (983.6 � 199.3 micg � h/L versus 697.6 � 133.0 mcg � h/L; P &lt; .05) and a 51% increase in sertraline terminal elimination half-life (t_1/2) (35.5 � 5.6 hours 2 versus 23.5 � 4.4 hours; P &lt; .01) compared with extensive metabolizers. The oral clearance (CL_oral) of sertraline in poor metabolizers was significantly lower than that in extensive metabolizers (105.3 � 19.4 L/h versus 148.4 � 28.6 L/h; P &lt; .05). The AUC0-144 and Cmax of desmethylsertraline in poor metabolizers were significantly lower than the values in extensive metabolizers (627.6 � 203.8 �g � h/L versus 972.1 � 270.3 �g � h/L; P &lt; .05; 23.6 � 6.5 nmol/L versus 32.4 � 8.2 nmol/L; P &lt; .01; respectively). In addition, desmethylsertraline Tmax (time to reach Cmax) in poor metabolizers was markedly higher than that in extensive metabolizers (70.0 � 24.5 hours versus 26.4 � 5.4 hours; P &lt; .01). None None Fluoxetine: Co-administration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29-44, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2-3 fold, and decreased the AUC of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to the previous level. None None None None Paroxetine: Co-administration of paroxetine (20 mg/day for 5-8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 resulted in increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6 fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with paroxetine. When paroxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to previous levels. Metabolism Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. None None Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. None None None None Quote: &quot;All six SSRIs inhibited the formation of ODV with PX being the most potent and DES being the least potent (Table 3).&quot; K_i for paroxetine vs O-desmethylvenlafaxine formation: 0.17micM None None Quote: &quot;All six SSRIs [including quinidine] inhibited the formation of ODV with PX being the most potent and DES being the least potent (Table 3).&quot; K_i for quinidine vs O-desmethylvenlafaxine formation: 0.04micM Metabolism In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4 None None Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels. Ketoconazole and Other CYP3A4 Inhibitors Coadministration of ketoconazole (200 mg/day for 14 days) with a 15 mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied. When ketoconazole is given concomitantly with aripiprazole, the aripiprazole dose should be reduced to one-half of its normal dose. Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; moderate inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. Quinidine and Other CYP2D6 Inhibitors Coadministration of a 10 mg single dose of aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 35%. Aripiprazole dose should be reduced to one-half of its normal dose when quinidine is given concomitantly with aripiprazole. Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. When adjunctive ABILIFY is administered to patients with Major Depressive Disorder, ABILIFY should be administered without dosage adjustment as specified in DOSAGE AND ADMINISTRATION (2.3). Carbamazepine and Other CYP3A4 Inducers Coadministration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg/day) resulted in an approximate 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced. None None None None Route of administration: oral study duration: Two phases : Phase I - a single dose of aripiprazole; Phase II - 7 days pre-treatment with ITZ, single dose of aripiprazole with ITZ, then ITZ alone or 14 more days; a 35 day washout between Phase I and II population: 24 healthy adult Japanese males meean age (SD): 23.2 (2.4) AUC_i/AUC (336hr): 1075/736 = 1.48 Description: The objective of the present study was to investigate the influence of itraconazole (hereafter referred to as ITZ) co-administration (CYP3A4 inhibition) on the pharmacokinetics of ARIPIPRAZOLE administered to 24 healthy adult male volunteers in a fasting condition. The influence of CYP3A4 inhibition was also examined by CYP2D6 genotype. All subjects were administered a single oral dose of ARIPIPRAZOLE alone in Period I and a single oral dose of ARIPIPRAZOLE following administration of ITZ at 100 mg/day for 7 consecutive days in Period II. The pharmacokinetic parameters of ARIPIPRAZOLE and its main metabolite OPC-14857 were determined. Co-administration of ITZ increased the Cmax, AUC336 hr, and t1/2,z of ARIPIPRAZOLE and OPC-14857 by 19.4%, 48.0%, and 18.6% and by 18.6%, 38.8%, and 53.4%, respectively. By co-administration of ITZ, the CL/F of ARIPIPRAZOLE in extensive metabolizers was decreased by 26.6%, with an even greater decrease (47.3%) in intermediate metabolizers. For the co-administration period, the CL/F of ARIPIPRAZOLE in intermediate metabolizers was about half of that in extensive metabolizers. For Cmax, there was no significant difference between extensive metabolizers and intermediate metabolizers, and the percent change by co-administration of ITZ was less than 20% in both extensive metabolizers and intermediate metabolizers. For OPC-14857, the t(max) in intermediate metabolizers was longer than that in extensive metabolizers, with the difference being amplified by co-administration of ITZ. The AUC336 hr showed similar increases by co-administration of ITZ in all genotypes. The urinary 6beta-hydroxycortisol/cortisol concentration ratio following ITZ administration for 7 consecutive days was about half of that before the start of ITZ administration, indicating that CYP3A4 metabolic activity was inhibited by administration of ITZ. The influence of CYP3A4 inhibition on the pharmacokinetics of ARIPIPRAZOLE was not considered to be clinically significant. On the other hand, definite differences in pharmacokinetics were observed between CYP2D6 genotypes. Enzyme system: human liver microsomes NADPH added: yes inhibitor used: ketoconazole reaction: clarithromycin --&gt; 14-(R)-hydroxylase-clarithromycin clarithromycin --&gt; 14-N-demethylase-clarithromycin description: clarithromycin oxidative metabolism was nearly completely wiped out by the addition of this selective inhibitor None None Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of both 14-(R)-hydroxylase-clarithromycin and 14-N-demethylase-clarithromycin in a recombinant cyp3a4 Supersome system None None None None Quote: To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved. METHODS: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction... Ketoconazole inhibition of N-dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N-dealkylation at therapeutically relevant concentrations.The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20-25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. None None Quote: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction. RESULTS: CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. route of administration: oral study duration: single dose of perphenazine (0.11 mg/kg orally) or placebo following a randomized double-blind design. Perphenazine plasma concentrations and effects were assessed for a period of 8 hours. Subsequently, subjects were treated with a standard therapeutic dose of paroxetine (20 mg/day orally) for 10 days and test sessions with perphenazine and placebo were repeated. population: 8 adults (5 female, 3 male); all CYP2D6 EMs as determined by the dextromethorphan metabolite ration ages: 21 - 49 Description: Paroxetine treatment resulted in a twofold to 21-fold decrease in CYP2D6 activity (p &lt; 0.001). After pretreatment with paroxetine, perphenazine peak plasma concentrations increased twofold to 13-fold (p &lt; 0.01). This was associated with a significant increase in central nervous system side effects of perphenazine, including oversedation, extrapyramidal symptoms, and impairment of psychomotor performance and memory (p &lt; 0.05). None None route of administration: oral study duration: single-dose of perphenazine (0.1mg/kg) population: 22 healthy, non-smoking, adult males of chinese ancestry tested for known CYP450 polymorphisms? yes...&quot;DNA samples from all participants were genotyped for CYP2D6*10 and CYP2D6*5 using a nested and allele- specific PCR-restriction fragment length polymorphism analysis as described previously [34,35]. Alleles not being CYP2D6*5 or CYP2D6*10 were called CYP2D6*1. Geno- typing for these three alleles has been shown in the past to be adequate for a reliable determination of CYP2D6 genotypes in Asians [8,15,34,35]. The invest igators did not have access to data on CYP2D6 genotype during ascertainment of the pharmacological phenotypes (i.e. perphenazine and prolactin concentration data); genotyping was also performed blind to the prolactin or plasma concentration data.&quot; ages: 21 - 50 description: &quot;In volunteers with CYP2D6*10/CYP2D6*10 genotype, the mean area under curve (AUC0-6) for perphenazine concentration was 2.9-fold higher than those who carry the CYP2D6*1 allele (P&lt;0.01).&quot; None None route of administration: oral study duration: During a 1-year period a blood sample was taken for genotyping together with blood for serum monitoring. Blood samples were taken from 151 patients population: patients undergoing therapeutic drug monitoring of orally-administered perphenazine. The analysis included 56 EMs and 3 PMs taking a drug that could potentially affect perphenazine metabolism, 32 EMs and 6 PMs taking a no drug known to affect perphenazine metabolism. All PMs were grouped for analysis since they did not carry a functional CYP2D6 allele. tested for known CYP450 polymorphisms? yes, genotyping found 142 CYP2D6 extensive metabolizers (EM) and 9 poor metabolizers (PM) ages: 12 - 75; median of 38 years description: The poor metabolizer group had the highest median steady-state serum concentration value (0.195 nmol/L per milligram), which was about twice the value of the extensive metablolizer group without potentially interacting medicine (0.098 nmol/L per milligram; p &lt; 0.01) None None Metabolism Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein. None None Drugs that affect drug metabolism via cytochrome P450: Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated. None None Drugs that affect drug metabolism via cytochrome P450: Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated. A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem tartrate (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0-inf of zolpidem tartrate. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance. None None Co-administration of a single dose of zolpidem tartrate with 4 doses of ketoconazole, a potent CYP3A4 inhibitor increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30%) along with an increase in the pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Patients should be advised that use of Edluar with ketoconazole may enhance the sedative effects. None None Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels. Ketoconazole and Other CYP3A4 Inhibitors Coadministration of ketoconazole (200 mg/day for 14 days) with a 15 mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. The effect of a higher ketoconazole dose (400 mg/day) has not been studied. When ketoconazole is given concomitantly with aripiprazole, the aripiprazole dose should be reduced to one-half of its normal dose. Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; moderate inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. Quinidine and Other CYP2D6 Inhibitors Coadministration of a 10 mg single dose of aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6, increased the AUC of aripiprazole by 112% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 35%. Aripiprazole dose should be reduced to one-half of its normal dose when quinidine is given concomitantly with aripiprazole. Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. When adjunctive ABILIFY is administered to patients with Major Depressive Disorder, ABILIFY should be administered without dosage adjustment as specified in DOSAGE AND ADMINISTRATION (2.3). Carbamazepine and Other CYP3A4 Inducers Coadministration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg/day) resulted in an approximate 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite, dehydro-aripiprazole. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced. None None Metabolism Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9 (CYP2C9) pathway. None None Drug Interactions In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a potent CYP3A4 inhibitor, increased the Cmax, AUC, and elimination half-life, and decreased clearance of trazodone after administration of ritonavir twice daily for 2 days. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole or nefazodone may lead to substantial increases in trazodone plasma concentrations, with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. Carbamazepine reduced plasma concentrations of trazodone when co-administered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs. None None None None Quote: risperidone was incubated with human liver microsomes in the presence of different concentrations of inhibitors of CYP enzymes. Both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A) inhibited the formation of 9-hydroxyrisperidone in a concentration-dependent manner (Fig. 4). None None Quote: Ketoconazole was a potent inhibitor of CPHP (4-(4-chlorophenyl)-4-hydroxypiperidine) formation with IC50 values of 0,10, 0,23 and 0,14 micM in microsomes HL-1, HL-6 and HL-9 respectively, wheras sulphaphenazole, furafylline and quinidine showed little inhibition (IC50 &gt; 100micM) 12.3 Pharmacokinetics Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. None None &quot; Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%).&quot; None None Metabolism After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. Zaleplon is metabolized to a lesser extent by cytochrome P450 (CYP) 3A4 to form desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zaleplon's metabolites are pharmacologically inactive. None None Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels. Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18-45, increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Iloperidone doses should be reduced by about one-half when administered with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole). Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. None None None None Quote: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction. RESULTS: CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. Approximately 7% of the normal population has a genetic defect that leads to reduced levels of activity of cytochrome P450IID6 isozyme. Such individuals have been referred to as &quot;poor metabolizers&quot; (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants. While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in thirteen PM subjects demonstrated altered pharmacokinetic properties compared to sixteen &quot;extensive metabolizers&quot; (EM): mean Cmax, AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group. This suggests that fluvoxamine is metabolized, at least in part, by IID6 isozyme. Caution is indicated in patients known to have reduced levels of P450IID6 activity and those receiving concomitant drugs known to inhibit this isozyme (e.g., quinidine). None None route of administration: oral study duration: single 50mg dose fluvoxamine population: 7 male and 7 female; 10 CYP2D6 EMs and four PMs according to debrisoquine metabolism. 5 EMs smoked during the study as did 3 PMs ages: 25 - 49 Description: Compared with nonsmoking extensive metabolizers, nonsmoking poor metabolizers had a statistically significant (p = 0.02, Mann-Whitney U test) about twofold higher maximum plasma concentration, longer half-life, and fivefold lower oral clearance of fluvoxamine. None None Metabolism Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein. None None None None Variability in metabolism � A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as �poor metabolizers� of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S�fluoxetine at a slower rate and thus achieved higher concentrations of S�fluoxetine. Consequently, concentrations of S�norfluoxetine at steady state were lower. The metabolism of R�fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non�2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady�state concentration rather than increasing without limit. route of administration: oral study duration: population: 20 healthy, non-smoking, males tested for known CYP450 polymorphisms? Yes, using debrisoquin / 4-hydroxydebrisoquin metabolite ratio; 10 were CYP2D6 EMs and 10 PMs ages: 18 - 32 description: &quot;Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero--&gt;infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p &lt; 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p &lt; 0.05). Norfluoxetine Cmax and AUCzero--&gt;t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p &lt; 0.05).&quot; None None Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of both 1'-OH-midazolam and 4-OH-midazolam in a recombinant cyp3a4 Supersome system None None 12.5 Drug-Drug Interactions ... PREVACID is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. None None Metabolism and Excretion Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. None None Ketoconazole: Cinacalcet AUC(0-inf) and Cmax increased 2.3 and 2.2 times, respectively, when a single 90 mg cinacalcet dose on Day 5 was administered to subjects treated with 200 mg ketoconazole twice daily for 7 days compared to 90 mg cinacalcet given alone. None None None None Quote: Chemical Inhibition of CT and DCT Biotransformation in Microsomes. At 10micM R- or S-CT, ketoconazole reduced reaction velocity to 55 to 60% of control, quinidine to 80% of control, and omeprazole to 80 to 85% of control (Fig. 6). When the R- and S-CT concentration was increased to 100 M, the degree of inhibition by ketoconazole increased, while inhibition by quinidine decreased (Fig. 6). These findings are consistent with the data from heterologously expressed CYP isoforms. 12.5 Drug-Drug Interactions ... PREVACID is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. None None None None thioridizine is listed in table 4 (p21) as a CYP2D6 substrate with a narrow therapeutic range &quot;Drugs That Inhibit Cytochrome P450 2D6 In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P450 2D6 isozyme activity. Thus, this study suggests that drugs that inhibit P450 2D6 or the presence of reduced activity levels of this isozyme will produce elevated plasma levels of thioridazine. Therefore, the co-administration of drugs that inhibit P450 2D6 with thioridazine and the use of thioridazine in patients known to have reduced activity of P450 2D6 are contraindicated.&quot; None None None None Pharmacokinetic-related Interactions Clozapine is a substrate for many CYP 450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes. None None Quote: Fluvoxamine inhibited the demethylation [of clozapine] by 34+/-27% at 1 micM and 53+/-28% at 10 micM...Fluvoxamine caused an inhibition by 12+/-21% and 22+/-18% at 1 and 10 micM respectively. Metabolism Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein. None None In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram. None None &quot;Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces.&quot; None None Metabolism and Excretion Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. None None Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. None None None None Quote: Incubations of MIR with human liver microsomes resulted in the formation of OHM, DMM, and MIR-N- oxide (Fig. 1). Quinidine (5 micM) and alpha-naphthoflavone (0.5 micM),specific inhibitors of CYP2D6 and CYP1A2, respectively, partially inhibited MIR-hydroxylation. Ketoconazole (1 micM), a specific inhibitor of CYP3A4, inhibited MIR-N-demethylation and MIR-N-oxidation. NOTE: lowest MIR concentration tested was 25 micM Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. None None Metabolism and Elimination ... In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase. None None None None Quote: &quot;The ability of specific CYP isoforms to metabolize ziprasidone was determined using recombinant CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. H.p.l.c.-radioactivity profiles of ziprasidone metabolites following incubation of [14C]-ziprasidone or [3H]-ziprasidone with CYP3A4 are shown in Figure 5(a) and (b), respectively. CYP3A4 catalysed the formation of the N-dealkylated metabolite (M5), as well as ziprasidone sulphone (M8) and ziprasidone sulphoxide (M10). These oxidative metabolites were not detected in incubations containing recombinant CYP1A2, CYP2C9, CYP2C19 or CYP2D6.&quot; None None Quote: Inhibition of metabolite formation by each inhibitor is summarized in Table 2. Ketoconazole (10micM) inhibited the formation of ziprasidone sulphoxide (sulphoxide and sulphone) by 79% and oxindole acetic acid N-dealkylated product) completely. Sulphaphenazole an furafylline did not inhibit the formation of ziprasidone sulphoxide. The formation of oxindole acetic acid was inhibited (~50%) by furafylline. The formation of ziprasidone metabolites was not inhibited by quinidine but rather increased. route of administration: oral study duration: population: 14 healthy, non-smoking, adults (6 male, 8 female); only 13 completed the study tested for known CYP450 polymorphisms? ages: 18 - 45 description: &quot;Co-administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,infinity) increased by 33%, from 899 ng ml(-1) h with placebo to 1199 ng ml(-1) h with ketoconazole. Mean Cmax increased by 34%, from 89 ng ml(-1) to 119 ng ml(-1), respectively. The treatment effect on both of these parameters was statistically significant (P&lt;0.02).&quot; None None &quot;Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using ZYPREXA and fluoxetine in combination, also refer to the Drug Interactions section of the package insert for Symbyax.&quot; None None None None Quote: Ketoconazole produced concentration-dependent inhibition of DCT formation (Figure 4). The mean (+/-SE) IC50 values for ketoconazole were 0.81 (+/-.24) micM/L at CT = 10 micM/L, and 1.54 (+/-.35) micM/L CT = 100 micM/L; these values were not significantly different. Metabolism and Elimination: ... Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite. None None None None Quote: In presence of erythromycin, activity of CYP3A4 decreased significantly; for QTP, C(max), AUC(0-24), and t(1/2) increased significantly, CL decreased significantly, and variations in AUC(0-24) and CL showed, respectively, significant negative and positive correlation to that of CYP3A4 activity; route of administration: oral study duration: An 8-day crossover trial -- in each branch participants were give 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. population:12 healthy male volunteers tested for known CYP450 polymorphisms? ages: mean 33 years description: ...concomitant use of ketoconazole resulted in substantial increases in plasma concentrations of quetiapine (Figure 3A). The mean Cmax and AUC of quetiapine were increased by 235% and 522%, respectively. Conversely, the geometric mean AUC and Cmax of the sulfoxide metabolite were decreased by 46% and 87%, respectively (Figure 3B). Mean CL/F of quetiapine was decreased by 84%, and mean t1/2 was increased from 2.61 to 6.76 h. None None Metabolism: ... In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. None None Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of N-Desmethyl diltiazem using a recombinant CYP3A5 Supersome system. None None Enzyme system: recombinant human enzymes in Supersomes NADPH added: yes inhibitor used: no This study showed the formation of N-Desmethyl diltiazem using a recombinant CYP3A4 Supersome system. None None &quot;Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite.&quot; None None None None Quote: Incubations of MIR with human liver microsomes resulted in the formation of OHM, DMM, and MIR-N- oxide (Fig. 1). Quinidine (5 micM) and alpha-naphthoflavone (0.5 micM),specific inhibitors of CYP2D6 and CYP1A2, respectively, partially inhibited MIR-hydroxylation. Ketoconazole (1 micM), a specific inhibitor of CYP3A4, inhibited MIR-N-demethylation and MIR-N-oxidation. NOTE: lowest MIR concentration tested was 25 micM Metabolism Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients’ plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein. None None CYP2D6 Inhibitors The potent CYP2D6 inhibitor, paroxetine (20 mg once daily), increases ranolazine concentrations 1.2-fold. No dose adjustment of Ranexa is required in patients treated with CYP2D6 inhibitors. None None None None Quote: To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved. METHODS: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction... Ketoconazole inhibition of N-dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N-dealkylation at therapeutically relevant concentrations.The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20-25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. None None Quote: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction. RESULTS: CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. 12.5 Drug-Drug Interactions ... PREVACID is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. None None None None Quote: &quot;Formation of NDV had a mean Vmax of 2.14 nmol min mg protein, and a mean Km of 2504 M (Table 2). Incubations of 750micM VF with SFZ and QUI led to 18% and 23% reduction in NDV production respectively, while increasing concentrations of ANA led to an 11% increase in NDV formation over baseline. KET [ketoconazole] had a more profound effect on NDV formation, leading to a 65% mean reduction in production of this metabolite (Figure 5).&quot; 7.5 Drugs metabolized by CYP2C19 In a clinical study in Japan evaluating rabeprazole in patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied. None None None None Quote: &quot;The ability of specific CYP isoforms to metabolize ziprasidone was determined using recombinant CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. H.p.l.c.-radioactivity profiles of ziprasidone metabolites following incubation of [14C]-ziprasidone or [3H]-ziprasidone with CYP3A4 are shown in Figure 5(a) and (b), respectively. CYP3A4 catalysed the formation of the N-dealkylated metabolite (M5), as well as ziprasidone sulphone (M8) and ziprasidone sulphoxide (M10). These oxidative metabolites were not detected in incubations containing recombinant CYP1A2, CYP2C9, CYP2C19 or CYP2D6.&quot; Enzyme system: human liver microsomes NADPH added: yes inhibitor used: sulphaphenazole reaction: clarithromycin --&gt; 14-(R)-hydroxylase-clarithromycin clarithromycin --&gt; 14-N-demethylase-clarithromycin description: clarithromycin oxidative metabolism was only very slightly affected by the addition of the selective inhibitor None None Enzyme system: recombinant human enzymes in human lymphoblastoid for CYP1A2 and CYP2D6; recombinant human enzymes in baculovirus-infected insect cells for CYP2C8, CYP2C9, and CYP2C19 NADPH added:yes inhibitor used: no When NEF or OH-NEF was incubated with microsomes from cells transfected with human cDNA for one of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP2C8, CYP2C9 arg, CYP2C9 cys, or CYP2C19, metabolite formation was seen with the CYP3A4 incubations only (Table 4). None None None None Quote: Incubations of human liver microsomes with NEF and the CYP3A4 inhibitor ketoconazole resulted in a concentration-dependent inhibition of the formation of mCPP and OH-NEF (Fig. 3). Incubations of human liver microsomes with NEF and the CYP2D6 inhibitor quinidine did not affect the production of OH-NEF and mCPP. Incubations of OH-NEF with the CYP3A4 inhibitor ketoconazole resulted in the inhibition of metabolite formation, and incubations with the CYP2D6 inhibitor quinidine did not, similar to what was found with NEF metabolism (data not presented). Route of administration: oral polymorphic enzyme: yes study duration: 100 mg desvenlafaxine on day 1 followed by 120 hours of PK data sampling; repeated on day 11 population: healthy adults, non-smokers (&gt; 1yr), genotyped (7 CYP2D6 extensive metabolizers and 7 poor metabolizers) ages: 18-55 description: Results: After administration of venlafaxine ER, mean Cmax and AUC of venlafaxine were significantly greater in PMs compared with EMs, whereas mean Cmax and AUC of its metabolite, desvenlafaxine, were significantly lower for PMs than for EMs (P = 0.001, all comparisons). In contrast, mean Cmax and AUC of desvenlafaxine after administration of desvenlafaxine were comparable between EMs and PMs. None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: recombinant human CYP2B6 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system FAILED TO catalyze the above reactions to any measurable extent None None None None Smoking Based on in vitro studies utilizing human liver enzymes, ziprasidone is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of ziprasidone. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any significant pharmacokinetic differences between smokers and nonsmokers. None None Quote: &quot;The ability of specific CYP isoforms to metabolize ziprasidone was determined using recombinant CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. H.p.l.c.-radioactivity profiles of ziprasidone metabolites following incubation of [14C]-ziprasidone or [3H]-ziprasidone with CYP3A4 are shown in Figure 5(a) and (b), respectively. CYP3A4 catalysed the formation of the N-dealkylated metabolite (M5), as well as ziprasidone sulphone (M8) and ziprasidone sulphoxide (M10). These oxidative metabolites were not detected in incubations containing recombinant CYP1A2, CYP2C9, CYP2C19 or CYP2D6.&quot; Enzyme system: recombinant human CYP2C19 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system FAILED TO catalyze the above reactions to any measurable extent None None Enzyme system: recombinant human enzymes in human lymphoblastoid NADPH added: not explicitly mentioned but assumed inhibitor used: no Quetiapine metabolites were not detected after 1-h incubations of quetiapine with microsomes from vector-control lymphoblastoid cell lines or those that expressed CYP1A2, CYP2C9, CYP2C19 or CYP2E1. In contrast, metabolite profles produced when quetiapine was incubated in human liver microsomes (Figure 2A) were similar to those produced by expressed CYP3A4 (Figure 2B). Quetiapine sulfoxide was the major metabolite formed during incubations with expressed CYP3A4. None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: human liver microsomes NADPH added: yes inhibitor used: alpha-napthoflavone reaction: alprazolam --&gt; 4-OH-alprazolam alprazolam --&gt; 1'-OH-alprazolam Inhibition of CYP1A2 by in vitro selective inhibitor alpha-napthoflavone had no effect on the transformation of alprazolam to its two major metabolites NOTE: the use of a NADPH generating system is inferred from paragraph 2 of p. 934 &quot;Alprazolam hydrozylase assay&quot; None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None None None Table 4 shows that paroxetine (20mg 1xd X 9) effected no increase (and in fact a slight decrease) of the AUC of asenapine in vivo Enzyme system: recombinant human enzymes in human lymphoblastoid NADPH added: not explicitly mentioned but assumed inhibitor used: no Quetiapine metabolites were not detected after 1-h incubations of quetiapine with microsomes from vector-control lymphoblastoid cell lines or those that expressed CYP1A2, CYP2C9, CYP2C19 or CYP2E1. In contrast, metabolite profles produced when quetiapine was incubated in human liver microsomes (Figure 2A) were similar to those produced by expressed CYP3A4 (Figure 2B). Quetiapine sulfoxide was the major metabolite formed during incubations with expressed CYP3A4. None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: recombinant human CYP2E1 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system FAILED TO catalyze the above reactions to any measurable extent None None None None Quote: &quot;The ability of specific CYP isoforms to metabolize ziprasidone was determined using recombinant CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. H.p.l.c.-radioactivity profiles of ziprasidone metabolites following incubation of [14C]-ziprasidone or [3H]-ziprasidone with CYP3A4 are shown in Figure 5(a) and (b), respectively. CYP3A4 catalysed the formation of the N-dealkylated metabolite (M5), as well as ziprasidone sulphone (M8) and ziprasidone sulphoxide (M10). These oxidative metabolites were not detected in incubations containing recombinant CYP1A2, CYP2C9, CYP2C19 or CYP2D6.&quot; Enzyme system: recombinant human enzymes in human lymphoblastoid for CYP1A2 and CYP2D6; recombinant human enzymes in baculovirus-infected insect cells for CYP2C8, CYP2C9, and CYP2C19 NADPH added:yes inhibitor used: no When NEF or OH-NEF was incubated with microsomes from cells transfected with human cDNA for one of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP2C8, CYP2C9 arg, CYP2C9 cys, or CYP2C19, metabolite formation was seen with the CYP3A4 incubations only (Table 4). None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: recombinant human enzymes in human lymphoblastoid for CYP1A2 and CYP2D6; recombinant human enzymes in baculovirus-infected insect cells for CYP2C8, CYP2C9, and CYP2C19 NADPH added:yes inhibitor used: no When NEF or OH-NEF was incubated with microsomes from cells transfected with human cDNA for one of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP2C8, CYP2C9 arg, CYP2C9 cys, or CYP2C19, metabolite formation was seen with the CYP3A4 incubations only (Table 4). None None Enzyme system: recombinant human enzymes in human lymphoblastoid cells NADPH added:yes inhibitor used: no Table 2 shows that CYP2C19, CYP2B6, CYP2A6, AND CYP3E1 each contributed less than 1% to the formation of metabolites by the three metabolic pathways examined. NOTE: Formation of MIR-N+-glucuronide, a metabolite found in significant concentrations in humans, was not examined however, this metabolite is likely the product of the either the dirct glucuronidation of mirtazapine or a metabolite produced by the three pathways examined. None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: recombinant human CYP2D6 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system FAILED TO catalyze the above reactions to any measurable extent None None Enzyme system: recombinant human CYP1A1 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system FAILED TO catalyze the above reactions to any measurable extent None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: recombinant human enzymes in human lymphoblastoid NADPH added: not explicitly mentioned but assumed inhibitor used: no Quetiapine metabolites were not detected after 1-h incubations of quetiapine with microsomes from vector-control lymphoblastoid cell lines or those that expressed CYP1A2, CYP2C9, CYP2C19 or CYP2E1. In contrast, metabolite profles produced when quetiapine was incubated in human liver microsomes (Figure 2A) were similar to those produced by expressed CYP3A4 (Figure 2B). Quetiapine sulfoxide was the major metabolite formed during incubations with expressed CYP3A4. None None Paroxetine Coadministration of a single dose of zaleplon 20 mg and paroxetine 20 mg daily for 7 days did not produce any interaction on psychomotor performance. Additionally, paroxetine did not alter the pharmacokinetics of zaleplon, reflecting the absence of a role of CYP2D6 in zaleplon's metabolism. None None Enzyme system: recombinant human enzymes in human lymphoblastoid cells NADPH added:yes inhibitor used: no Table 2 shows that CYP2C19, CYP2B6, CYP2A6, AND CYP3E1 each contributed less than 1% to the formation of metabolites by the three metabolic pathways examined. NOTE: Formation of MIR-N+-glucuronide, a metabolite found in significant concentrations in humans, was not examined however, this metabolite is likely the product of the either the dirct glucuronidation of mirtazapine or a metabolite produced by the three pathways examined. None None &quot;Cytochrome P450 3A4: In vitro and in vivo data indicate that rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole). Ketoconazole: Coadministration of ketoconazole (200 mg twice daily for 7 days) with rosuvastatin (80 mg) resulted in no change in plasma concentrations of rosuvastatin. Erythromycin: Coadministration of erythromycin (500 mg four times daily for 7 days) with rosuvastatin (80 mg) decreased AUC and Cmax of rosuvastatin by 20% and 31%, respectively. These reductions are not considered clinically significant.&quot; None None Enzyme system: recombinant human enzymes in human lymphoblastoid NADPH added: not explicitly mentioned but assumed inhibitor used: no Quetiapine metabolites were not detected after 1-h incubations of quetiapine with microsomes from vector-control lymphoblastoid cell lines or those that expressed CYP1A2, CYP2C9, CYP2C19 or CYP2E1. In contrast, metabolite profles produced when quetiapine was incubated in human liver microsomes (Figure 2A) were similar to those produced by expressed CYP3A4 (Figure 2B). Quetiapine sulfoxide was the major metabolite formed during incubations with expressed CYP3A4. None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: recombinant human enzymes in human lymphoblastoid for CYP1A2 and CYP2D6; recombinant human enzymes in baculovirus-infected insect cells for CYP2C8, CYP2C9, and CYP2C19 NADPH added:yes inhibitor used: no When NEF or OH-NEF was incubated with microsomes from cells transfected with human cDNA for one of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP2C8, CYP2C9 arg, CYP2C9 cys, or CYP2C19, metabolite formation was seen with the CYP3A4 incubations only (Table 4). None None Enzyme system: recombinant human enzymes in human lymphoblastoid for CYP1A2 and CYP2D6; recombinant human enzymes in baculovirus-infected insect cells for CYP2C8, CYP2C9, and CYP2C19 NADPH added:yes inhibitor used: no When NEF or OH-NEF was incubated with microsomes from cells transfected with human cDNA for one of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP2C8, CYP2C9 arg, CYP2C9 cys, or CYP2C19, metabolite formation was seen with the CYP3A4 incubations only (Table 4). None None Enzyme system: recombinant human CYP2C9 enzymes in insect microsomes NADPH added: yes substrate used: atorvastatin acid and lactone reaction: atorvastatin acid--&gt;ortho-hydroxy-atorvastatin atorvastatin lactone--&gt;ortho-hydroxy-atorvastatin atorvastatin acid--&gt;para-hydroxy-atorvastatin atorvastatin lactone--&gt;para-hydroxy-atorvastatin description: This enzyme system FAILED TO catalyze the above reactions to any measurable extent None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Enzyme system: human liver microsomes NADPH added: yes inhibitor used: quinidine reaction: clarithromycin --&gt; 14-(R)-hydroxylase-clarithromycin clarithromycin --&gt; 14-N-demethylase-clarithromycin description: clarithromycin oxidative metabolism was only very slightly affected by the addition of the selective inhibitor None None Enzyme system: recombinant human enzymes in human lymphoblastoid cells NADPH added:yes inhibitor used: no Table 2 shows that CYP2C19, CYP2B6, CYP2A6, AND CYP3E1 each contributed less than 1% to the formation of metabolites by the three metabolic pathways examined. NOTE: Formation of MIR-N+-glucuronide, a metabolite found in significant concentrations in humans, was not examined however, this metabolite is likely the product of the either the dirct glucuronidation of mirtazapine or a metabolite produced by the three pathways examined. None None Enzyme system: recombinant human enzymes in human lymphoblastoid cells NADPH added:yes inhibitor used: no Table 2 shows that CYP2C19, CYP2B6, CYP2A6, AND CYP3E1 each contributed less than 1% to the formation of metabolites by the three metabolic pathways examined. NOTE: Formation of MIR-N+-glucuronide, a metabolite found in significant concentrations in humans, was not examined however, this metabolite is likely the product of the either the dirct glucuronidation of mirtazapine or a metabolite produced by the three pathways examined. None None Enzyme system: human liver microsomes NADPH added: yes inhibitor used: furafylline reaction: clarithromycin --&gt; 14-(R)-hydroxylase-clarithromycin clarithromycin --&gt; 14-N-demethylase-clarithromycin description: clarithromycin oxidative metabolism was only very slightly affected by the addition of the selective inhibitor None None Ketoconazole Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. None None Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None None None Quote: &quot;The ability of specific CYP isoforms to metabolize ziprasidone was determined using recombinant CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. H.p.l.c.-radioactivity profiles of ziprasidone metabolites following incubation of [14C]-ziprasidone or [3H]-ziprasidone with CYP3A4 are shown in Figure 5(a) and (b), respectively. CYP3A4 catalysed the formation of the N-dealkylated metabolite (M5), as well as ziprasidone sulphone (M8) and ziprasidone sulphoxide (M10). These oxidative metabolites were not detected in incubations containing recombinant CYP1A2, CYP2C9, CYP2C19 or CYP2D6.&quot; Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely. None None Route of administration: fluconazole oral; warfarin - IV study duration: phase 1 - 8 days of .75mg/kg warfarin alone; phase 2 (21 days later) 14 days of .75mg/kg q.d. AND 400mg q.d. of fluconazole population: 6 male ages: 23-29 description: formation of 6- and 7-OH-(s)-warfarin decreased by 70%; this reaction is considered primarily catalyzed by CYP2C9. There was also a notable increase in AUC of (S)-warfarin (mean AUC_i/AUC=7.633) None None 'The FDA recommends this as a CYP2C9 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None Metabolism Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9 (CYP2C9) pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved total plasma concentrations None None 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None Drug Interactions Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo. Ritonavir also inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A. Co-administration of ritonavir and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse effects None None None None Table 3 shows that the AUC of sildenafil increased 11-fold in the presence of ritonavir None None The FDA notes that this is a &quot;moderate&quot; CYP3A inhibitor in vivo in it most recent guidance document. See Table 5, p22 None None The FDA notes that this is a &quot;moderate&quot; CYP3A inhibitor in vivo in it most recent guidance document. See Table 5, p22 None None Quote: In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo...Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. None None Quote: &quot;The pharmacokinetic and pharmacodynamic interaction between azithromycin (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-70-8), a short-acting hypnotic agent, was investigated in an open, three-way cross-over study, including erythromycin (CAS 114-07-8) as a positive control. Twelve healthy male and female subjects had standard doses of azithromycin (500 mg o.d. over 3 days), or erythromycin (500 mg t.i.d. over 5 days), or no pretreatment. On the day of the last dose, they ingested 15 mg midazolam. Blood samples were collected and psychometric tests performed. Erythromycin pretreatment (E) significantly changed the pharmacokinetics of midazolam compared to control (C), whereas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h.ng.ml-1 vs. (E) 662.7 h.ng.ml-1*+ and (A) 220.0 h.ng.ml-1; concentration maxima (C) 67.2 ng.ml-1 vs. (E) 182.3 ng.ml-1*+ and (A) 86.7 ng.ml-1; elimination half-life (C) 2.21 h vs. (E) 4.85 h* and (A) 2.41 h (* p &lt; 0.05 vs. (C), +p &lt; 0.05 vs. (A)). Pharmacodynamic tests (digit symbol substitution test; critical flicker fusion test; subjective analog scale for rating of alertness; duration of sleep) consistently showed significant differences after erythromycin pretreatment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.&quot; None None Route of administration: oral study duration: read description below population: (fluoxetine group) 14 healthy volunteers (7 male and 7 female), all extensive metabolizers of dextromethorphan ages: mean(std dev): 26 (unknown) Description: In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t(1/2)inh) revealed the time course of fluoxetine inhibition (t(1/2)inh = 7.0 +/- 1.5 days) to be significantly longer than either paroxetine (t(1/2)inh = 2.9 +/- 1.9) or sertraline (t(1/2)inh = 3.0 +/- 3.0) (p &lt; 0.01), but the latter were not significantly different from each other (p &gt; 0.05). Time for the extrapolated DMR versus time log-linear plots to return to baseline was significantly different between fluoxetine (63.2 +/- 5.6 days) and both paroxetine (20.3 +/- 6.4 days) and sertraline (25.0 +/- 11.0 days) (p &lt; 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine &gt; sertraline &gt;or= paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. Drugs metabolized by CYP2D6 � Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued (see CONTRAINDICATIONS and WARNINGS). None None route of administration: oral study duration: fluoxetine 80mg qd for eight days population: 32 healthy adults, all extensive CYP2D6 metabolizers based on DM:DX ages: unmentioned Description: The urinary concentration ratio of dextromethorphan:dextrorphan (interpreted as an in vivo index of CYP2D6 activity) was determined for each subject before and after the 8 days of receiving SSRIs. Plasma SSRI trough concentrations were measured on days 6-9. The CYP2D6 genotype was determined in a subject with an undetectable paroxetine concentration. Inhibition of CYP2D6 correlated significantly with plasma concentrations of paroxetine and fluoxetine. In contrast, no significant correlations emerged between CYP2D6 inhibition and plasma concentrations of sertraline or fluvoxamine. The subject with an undetectable paroxetine concentration was found to carry at least three functional CYP2D6 genes. None None Route of administration: oral study duration: four phase crossover study; each phase consisted of four days pre-treatment with placebo or fluconazole (50,100, or 200mg), on day four 0.25mg of triazolam was administered population: 8 healthy adults male:3 female:5 ages: 20-32 AUC_i/AUC (0-inf): 50mg fluconazole = 1.63 100mg fluconazole = 2.05 200mg fluconazole = 4.42 description: None None Route of administration: oral study duration: 4-way crossover; subjects received oral fluconazole (100, 200, or 400mg) or placebo; 2 hours later a single dose of MDZ (1mg IV or oral depending on the study arm) was given followed 30 minutes later by 4mg IV of ondansetron, followed by 15ug/kg of IV alfentanil (one arm) or 40mcg oral alfentanil. population: 6 male, 6 female ages: 19-36 AUC_i/AUC (0-inf; oral dosing; 100mg fluconazole): 46.1/21.3 AUC_i/AUC (0-inf; oral dosing; 200mg fluconazole): 70.7/21.3 AUC_i/AUC (0-inf; oral dosing; 400mg fluconazole): 105/21.3 None None None None The FDA notes that this is a &quot;moderate&quot; CYP3A inhibitor in vivo in it most recent guidance document. See Table 5, p22 Metabolism Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites which are excreted in the feces. The metabolites of zafirlukast identified in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast excreted in the feces are formed through the cytochrome P450 2C9 (CYP2C9) pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved total plasma concentrations None None Drug-Drug Interactions: ... Coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin (a substrate of CYP2C9) resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time increased by approximately 35%. The pharmacokinetics of zafirlukast were unaffected by coadministration with warfarin. None None Fluvoxamine is listed as a recommended inhibitor of CYP2C19 for in vivo studies in Table 2 (p. 19). Typically, this would qualify it as a in vivo selective inhibitor however, Table 2 also shows fluvoxamine as a recommended inhibitor of CYP1A2. None None (table from section &quot;Drug Interactions&quot;) Based on a finding of substantial interactions of fluvoxamine with certain of these drugs (see later parts of this section and also WARNINGS for details) and limited in vitro data for the IIIA4 isozyme, it appears that fluvoxamine inhibits the following isozymes that are known to be involved in the metabolism of the listed drugs: IA2 IIC9 IIIA4 IIC19 Warfarin Warfarin Alprazolam Omeprazole Theophylline Propranolol Tizanidine None None None None The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. type: Non_traceable_Drug_Label_Statement None None None None The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. None None Drug Interactions ... In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with PROVIGIL and may require dosage reduction and monitoring for toxicity. None None Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in Cmax of dextromethorphan. None None None None The FDA notes that this is a &quot;moderate&quot; CYP1A2 inhibitor in vivo in it most recent guidance document. See Table 6, p23 Cytochrome P450 (CYP450) Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug. None None None None The FDA notes that this is a &quot;moderate&quot; CYP1A2 inhibitor in vivo in it most recent guidance document. See Table 6, p23 None None Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. None None Table 3 shows that the AUC of desipramine increased 145% in the presence of ritonavir 7.2 Effects of Ranolazine on Other Drugs In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. None None None None Route of administration: oral polymorphic enzyme: NO study duration: 3 day pretreatment with diltiazem population: 7 male ages: 20-22 description: We investigated the interaction between triazolam and diltiazem in a randomized, three-phase crossover study. Seven healthy male volunteers received orally either a single 0.25 mg dose of triazolam, a 0.25 mg dose of triazolam after a 3-day treatment of diltiazem (180 mg day-1), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24 h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8 h. RESULTS: Diltiazem pretreatment significantly increased the area under the triazolam concentration-time curve (8.0 +/- 2.4 to 18.2 +/- 3.1 ng ml-1 h; P < 0.001; mean +/- s.d.). Peak triazolam concentration was increased (2.1 +/- 0.7 to 3.6 +/- 1.0 ng ml-1, P < 0.05) and the elimination half-life prolonged (4.1 +/- 2.1 to 7.6 +/- 1.9 h; P < 0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group. 7. DRUG INTERACTIONS ... In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6. None None route of administration: oral study duration: Controls: a single dose of 50 mg immediate-release metoprolol was given after 7-days of placebo. Exposed: a single dose of 50 mg immediate-release metoprolol was given after 7-days of 400 mg/day of celecoxib. population: 12 male volunteers tested for known CYP450 polymorphisms? Yes, all participants were genotyped as having heterozygous or homozygous extensive metabolizing CYP2D6 alleles. Participants CYP2C9 was also genotyped but no classification of the alleles appears in the paper. ages: mean age 30.7 +/- 5.3 description: Celecoxib increased the AUC(0-inf) of metoprolol signi&amp;#64257;cantly in all 12 volunteers, by 64.4% +/-57.0% (P &lt; .001). None None None None The FDA recommends this as a CYPC9 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19 Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes. None None None None The FDA notes that this is a weak CYP2D6 inhibitor for in vivo studies in it most recent guidance document. See Table 6, p. 23 Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes. None None None None Sertraline is listed as a moderate inhibitor in Table 6 (p23) but does not show up in Table 2 (a table listing several selective in viVo inhibitors) None None Route of administration: oral study duration: read description below population: (sertraline group) 12 healthy volunteers (8 male and 4 female), all extensive metabolizers of dextromethorphan ages: mean(std dev): 27 (unknown) Description: In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t(1/2)inh) revealed the time course of fluoxetine inhibition (t(1/2)inh = 7.0 +/- 1.5 days) to be significantly longer than either paroxetine (t(1/2)inh = 2.9 +/- 1.9) or sertraline (t(1/2)inh = 3.0 +/- 3.0) (p &lt; 0.01), but the latter were not significantly different from each other (p &gt; 0.05). Time for the extrapolated DMR versus time log-linear plots to return to baseline was significantly different between fluoxetine (63.2 +/- 5.6 days) and both paroxetine (20.3 +/- 6.4 days) and sertraline (25.0 +/- 11.0 days) (p &lt; 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine &gt; sertraline &gt;or= paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. Drugs Metabolized by P450 2D6 Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of coadministered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the coadministered drug. There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with sertraline may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from cotherapy, an increased dose of the coadministered drug may be required (see PRECAUTIONS: Drug Interactions: Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder). None None Effects of Voriconazole on Other Drugs In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes. None None 'The FDA recommends this as a CYP3A inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None 'The FDA recommends this as a CYP3A inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS and WARNINGS). Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6. None None None None Sildenafil: The results of one published study in HIV-infected men (n=6) indicated that coadministration of indinavir (800 mg every 8 hours chronically) with a single 25-mg dose of sildenafil resulted in an 11% increase in average AUC0-8hr of indinavir and a 48% increase in average indinavir peak concentration (Cmax) compared to 800 mg every 8 hours alone. Average sildenafil AUC was increased by 340% following coadministration of sildenafil and indinavir compared to historical data following administration of sildenafil alone (see WARNINGS, Drug Interactions and PRECAUTIONS, Drug Interactions). None None The FDA notes that this is a &quot;weak&quot; CYP1A2 inhibitor in vivo in it most recent guidance document. See Table 6, p23 None None The FDA notes that this is a &quot;weak&quot; CYP2C8 inhibitor in vivo in it most recent guidance document. See Table 6, p23 Effects of Voriconazole on Other Drugs In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes. None None Route of administration: oral polymorphic enzyme: NO study duration: 2 days ketoconazole pretreatment population: 8 male, 13 female ages:23-55 description: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). None None Route of administration: oral polymorphic enzyme: NO study duration: 12 days population: 17 male, 23 female ages:18-50 description: Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole... None None None None ketoconazole-janssen-2006-daily-med Label date: 08/2006 Date of DIKB entry: 05/21/2007 Ambiguous statement? NO description: Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of NIZORAL� Tablets and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects. Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary. Drug Interactions Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of ketoconazole tablets and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects. Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary. None None None None The FDA notes that this is a &quot;moderate&quot; CYP3A inhibitor in vivo in it most recent guidance document. See Table 5, p22 None None The FDA notes that this is a &quot;weak&quot; CYP1A2 inhibitor in vivo in it most recent guidance document. See Table 6, p23 Drug Interactions ... Amiodarone is also known to be an inhibitor of CYP3A4. Therefore, amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP3A4. While only a limited number of in vivo drug-drug interactions with amiodarone have been reported, the potential for other interactions should be anticipated. This is especially important for drugs associated with serious toxicity, such as other antiarrhythmics. If such drugs are needed, their dose should be reassessed and, where appropriate, plasma concentration measured. In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone. None None Route of administration: oral polymorphic enzyme: NO study duration: 5 day petreatment with clarithromycin population: 4 male, 8 female ages:24-53 In an open randomized crossover study of 3 phases 12 healthy volunteers received either clarithromycin (250 mg twice a day for 5 days), azithromycin (500 mg once a day for 3 days) or no pretreatment. On the last day of antibiotic treatment they ingested 15 mg midazolam. Plasma samples were collected for midazolam analysis up to 24 h and pharmacodynamic performance measured by a series of tests up to 12 h. Pretreatment with clarithromycin caused large and statistically significant changes in both the pharmacokinetic and pharmacodynamic parameters of midazolam compared to control. For example, the AUC was increased from 248.84-888.75 hng/ml (factor of 3.57, p < 0.0001) and the mean duration of sleep increased from 135.4 min to 281.3 min (p < 0.05). None None 'The FDA recommends this as a CYP3A inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin. None None 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin. None None None None duloxetine is listed as a moderate inhibitor in Table 6 (p23) but does not show up in Table 2 (a table listing several selective in viVo inhibitors) 7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions (5.10)]. None None route of administration: oral study duration: &quot;Study 1 was conducted in 2 distinct periods separated by a 7-day washout. In period 1, a single 50-mg dose of desipramine was administered, and blood samples were obtained for the measurement of desipramine plasma concentrations immediately before the dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hours after dosing. In period 2, duloxetine was administered at an initial dose of 40 mg twice daily. Subjects who did not tolerate this dose were allowed to have the dose lowered to 20 mg twice daily for up to 5 doses, after which dosing at 40 mg twice daily was resumed. On the seventh day of duloxetine dosing (day 14 of the overall protocol), the dose was increased to 60 mg twice daily and was continued at that level for an additional 14 days. On day 21 of the overall protocol (day 8 of duloxetine 60 mg twice daily dosing), a 50-mg dose of desipramine was administered. Blood samples were drawn to determine desipramine plasma concentrations as described for period 1, with additional samples at 168 and 192 hours after the desipramine dose. On the day before and the day of the period 2 desipramine dose (protocol days 20 and 21), blood samples for the measurement of duloxetine plasma concentrations were drawn immediately before duloxetine administration and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after administration.&quot; population: 14 healthy, non-smoking, adults; 7 male, 7 female; nearly all were of apparent European decent (&quot;white&quot;) tested for known CYP450 polymorphisms? yes but exact genotype not mentioned only that all were genotypically CYP2D6 extensive metabolizers. ages: 21 - 63 description: &quot;Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold.&quot; None None 7.19 Drugs Metabolized by Cytochrome P4502D6 In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6. None None Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150mg twice daily followed by a single dose of 50mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied. None None route of administration: oral study duration: &quot;dextromethorphan (30-mg oral dose) was administered to smokers at baseline and after 17 days of treatment with either bupropion sustained-release (150 mg twice daily) or matching placebo. Subjects quit smoking 3 days before the second dextromethorphan administration.&quot; population: 21 smoking, 9 female, 11 male tested for known CYP450 polymorphisms? yes ... all participants were considered CYP2D6 extensive metabolizers according to dextromethorphan:dextrorphan metabolite ratio ages: 21 - 40 NOTE: &quot;24-hour period preceding each laboratory visit. Two subjects reported taking medications that could potentially affect CYP2D6 metabolism and therefore alter bupropion concentrations (one reported use of hormone replacement therapy and another oral contraceptives).&quot; description: &quot;Among those taking bupropion, DM/DX ratio in- creased significantly at the second assessment relative to the first (0.012 � 0.012 vs. 0.418 � 0.302; P &lt; 0.0004) (Fig. 1). No such change was observed in those randomized to placebo (0.009 � 0.010 vs. 0.017 � 0.015; P = NS). Of those receiving bupropion, 46% (6/13) were phenotypically poor metabolizers after treatment.&quot; None None 'The FDA recommends this as a CYP2C8 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None None None Warfarin When fluvoxamine maleate (50 mg tid) was administered concomitantly with warfarin for 2 weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets. 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None Midazolam Concomitant administration of telithromycin with intravenous or oral midazolam resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam due to inhibition of CYP 3A4-dependent metabolism of midazolam. None None Drug interactions Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system. Co-administration of KETEK tablets and a drug primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentration of the drug co-administered with telithromycin that could increase or prolong both the therapeutic and adverse effects. Therefore, appropriate dosage adjustments may be necessary for the drug co-administered with telithromycin. None None Route of administration: oral polymorphic enzyme: no study duration: this was a matched pair study; 7 patients already take atorvastatin were matched with patients who were not taking atorvastatin or any other known CYP3A4 inhibitor. Of the patients taking atorvastatin, 5 were on 10mg/day, 1 on 20mg/day, and one on 40mg/day. All patient's received a .25mg/kg bolus of IV midazolam. population: 14 individuals; 10 male, 4 female ages: generally older ~61 (unfortunately ages given in mean/std dev) AUC_i/AUC of midazolam: 889.4/629.1=1.41 None None None None Quinidine is not metabolized by cytochrome P450IID6, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450IID6. Fluvoxamine is listed as a recommended inhibitor of CYP1A2 for in vivo studies in Table 2 (p. 19). Typically, this would qualify it as a in vivo selective inhibitor however, Table 2 also shows fluvoxamine as a recommended inhibitor of 2C19. None None None None Theophylline The effect of steady-state fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy nonsmoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate tablets. route of administration: oral study duration: single-dose theophylline (250 mg) after taking fluvoxamine for 9 days at 3 doses (0, 25, or 75 mg/day) in a randomized crossover design population: 9 healthy non-smoking volunteers (5 male, 4 female) participants tested known CYP450 phenotypes? No ages: 23 - 40 Description: Table II shows AUC_i/AUC (0-48) for theophylline as follows: fluvoxamine @ 25mg/day for 9 days: 504/349 = 1.44 fluvoxamine @ 75mg/day for 9 days: 710/349 = 2.03 None None Drug Interactions ... Desipramine: The effect of cinacalcet (90 mg) on the pharmacokinetics of desipramine (50 mg) has been studied in healthy subjects who were CYP2D6 extensive metabolizers. The AUC and Cmax of desipramine increased by 3.6 (296.5-446.7%) and 1.75 (157.5-194.9%) fold, respectively, in the presence of cinacalcet. This indicates that cinacalcet is a strong in vivo inhibitor of CYP2D6 and can increase the blood concentrations of drugs metabolized by CYP2D6. None None route of administration: oral study duration: controls: a single dose of 50 mg of desipramine alone; exposed: a single dose of 50 mg of desipramine after seven days of 90 mg cinacalcet. The groups were randomized and then alternated after a 10-day washout period. population: 14 healthy subjects; non-smokers; 8 female, 7 male tested for known CYP450 polymorphisms? subjects were required to be CYP2D6 extensive metabolizers based on genotyping ages: 18 - 55 description: Relative to when desipramine was administered alone, a 3.6-fold increase in AUC(0-inf) and 1.8-fold increase in Cmax of desipramine was observed when cinacalcet was administered for 5 days before and 2 days after dosing with desipramine (Table 1, Fig. 1). Administration with cinacalcet resulted in an increase in the AUC(0-inf) and Cmax of desipramine for all subjects (Fig. 2). Coadministration of desipramine and cinacalcet also resulted in a notable reduction in desipramine oral clearance. The terminal half-life of desipramine was also increased by approximately twofold when desipramine was coadministered with cinacalcet. The median tmax was 6 h following administration of desipramine alone and following administration with cinacalcet. None None route of administration: oral study duration: Each subject received 50 mg of cinacalcet (25-mg [as free base] film tablets, Kirin Brewery Co, Ltd, Tokyo, Japan) or a matched placebo orally once daily for 8 days. On day 8, each subject also received a single oral dose of 30 mg DEX (Medicon, 15-mg film tablets, Shionogi &amp; Co, Ltd, Osaka, Japan). population: 23 male volunteers tested for known CYP450 polymorphisms? all participants included in the PK analaysis wer classified as a CYP2D6 extensive metabolizers based on the dextromethorphan/dextorpham metabolic ratio ages: 20 - 33 description: The Cmax, AUC(0-t), and AUC(0-inf) of DEX were significantly higher during the cinacalcet treatment than with placebo, with a ratio of 7.481, 14.373, and 11.475, respectively. The Cmax of DOR was decreased, and the AUC(0-t) and AUC(0-inf) of DOR were slightly increased during cinacalcet treatment. None None None None The FDA notes that this is a &quot;weak&quot; CYP1A2 inhibitor in vivo in it most recent guidance document. See Table 6, p23 Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. None None None None The FDA notes that this is a &quot;weak&quot; CYP3A inhibitor in vivo in it most recent guidance document. See Table 5, p22 None None The FDA notes that this is a &quot;weak&quot; CYP3A inhibitor in vivo in it most recent guidance document. See Table 5, p22 Effects of Voriconazole on Other Drugs In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes. None None 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None 7.2 Effects of Ranolazine on Other Drugs In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. None None 7.2 Effects of Ranolazine on Other Drugs In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. None None None None The FDA notes that this is a &quot;moderate&quot; CYP1A2 inhibitor in vivo in it most recent guidance document. See Table 6, p23 Concurrent use of mexiletine and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35 to 136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting mexiletine. Theophylline plasma levels returned to pre-mexiletine values within 48 hours after discontinuing mexiletine. If mexiletine and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in theophylline dose should be considered. None None Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of mexiletine. None None Drug Interactions: Concomitant administration of SPORANOX� (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. None None 'The FDA recommends this as a CYPC19 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None 'The FDA recommends this as a CYP3A4/5 inhibitor for in vivo studies in it most recent guidance document. See Table 2, p. 19' None None CYP3A4 Isozyme�Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. This is consistent with the interactions observed between nefazodone and triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugs metabolized by this isozyme. Consequently, caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by CYP3A4. In particular, the combined use of nefazodone with triazolam should be avoided for most patients, including the elderly. The combined use of nefazodone with terfenadine, astemizole, cisapride, or pimozide is contraindicated (see CONTRAINDICATIONS and WARNINGS). None None None None Triazolam When a single oral 0.25 mg dose of triazolam was coadministered with nefazodone (200 mg BID) at steady state, triazolam half-life and AUC increased 4-fold and peak concentrations increased 1.7-fold. Nefazodone plasma concentrations were unaffected by triazolam. Coadministration of nefazodone potentiated the effects of triazolam on psychomotor performance tests. If triazolam is coadministered with nefazodone, a 75% reduction in the initial triazolam dosage is recommended. Because not all commercially available dosage forms of triazolam permit sufficient dosage reduction, coadministration of triazolam with nefazodone should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with nefazodone may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS). None None The FDA notes that this is a &quot;moderate&quot; CYP2D6 inhibitor in vivo in it most recent guidance document. See Table 6, p23 Drug Interactions In vivo studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs predominantly metabolized by the CYP450 2D6 isozyme include the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C (e.g., flecainide and propafenone) and monoamine oxidase inhibitors Type B. Coadministration of LAMISIL� should be done with careful monitoring and may require a reduction in dose of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2-fold increase in Cmax and a 5-fold increase in AUC. In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of LAMISIL�. None None None None Route of administration: oral study duration: read description below population: (paroxetine group) 13 healthy volunteers (8 male and 5 female), all extensive metabolizers of dextromethorphan ages: mean(std dev): 28 (unknown) Description: In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t(1/2)inh) revealed the time course of fluoxetine inhibition (t(1/2)inh = 7.0 +/- 1.5 days) to be significantly longer than either paroxetine (t(1/2)inh = 2.9 +/- 1.9) or sertraline (t(1/2)inh = 3.0 +/- 3.0) (p &lt; 0.01), but the latter were not significantly different from each other (p &gt; 0.05). Time for the extrapolated DMR versus time log-linear plots to return to baseline was significantly different between fluoxetine (63.2 +/- 5.6 days) and both paroxetine (20.3 +/- 6.4 days) and sertraline (25.0 +/- 11.0 days) (p &lt; 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine &gt; sertraline &gt;or= paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. route of administration: oral study duration: paroxetine 20mg qd for eight days population: 32 healthy adults, all extensive CYP2D6 metabolizers based on DM:DX ages: unmentioned Description: The urinary concentration ratio of dextromethorphan:dextrorphan (interpreted as an in vivo index of CYP2D6 activity) was determined for each subject before and after the 8 days of receiving SSRIs. Plasma SSRI trough concentrations were measured on days 6-9. The CYP2D6 genotype was determined in a subject with an undetectable paroxetine concentration. Inhibition of CYP2D6 correlated significantly with plasma concentrations of paroxetine and fluoxetine. In contrast, no significant correlations emerged between CYP2D6 inhibition and plasma concentrations of sertraline or fluvoxamine. The subject with an undetectable paroxetine concentration was found to carry at least three functional CYP2D6 genes. None None None None Quote: To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine...Time-dependent inhibition was demonstrated with an apparent K(I) of 4.85 microM and an apparent k(INACT) value of 0.17 min(-1). Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. ...In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine. route of administration: oral study duration: population: 17 males, 9 sparteine EMs and 8 sparteine PMs ages: 20-24 Description: During paroxetine, the median clearances were 22 l.h-1 and 18 l.h-1 in EMs and PMs respectively. The 5-fold decrease in clearance in EMs when desipramine was co-administered with paroxetine confirms that paroxetine is a potent inhibitor of CYP2D6. The lack of effect on clearance in PMs shows that paroxetine is a selective inhibitor of CYP2D6, which is absent from the livers of PMs. Before paroxetine, the median of desipramine clearance via 2-hydroxylation was 40-times higher in EMs than in PMs (56 and 1.4 l.h-1 respectively), but during paroxetine, it was only 2-times higher (6 and 2.9 l.h-1 respectively). None None Drug-Drug Interactions In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions). None None Amiodarone may suppress certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes. None None Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None None None Theophylline When nefazodone (200 mg BID) was given to patients being treated with theophylline (600 to 1200 mg/day) for chronic obstructive pulmonary disease, there was no change in the steady-state pharmacokinetics of either nefazodone or theophylline. FEV1 measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (i.e., when theophylline was administered alone). Therefore, dosage adjustment is not necessary for either drug when coadministered. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Quote: Mirtazapine reduced the rate of the reaction by much less than 50% even at concentrations of 250micM (see Table 3). In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Quote: No inhibition was found in microsomal preparations made from human livers with adequate CYP2D6 activity or with expressed CYP2D or with adequate activity of CYPs 1A2, 2A6, 2C9, 2E1, and 3A4. In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4. None None Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates.Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None 7.12 Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None None None Quote: CYP2D6 Activity. No significant effects on the formation of 1 -hydroxylated bufuralol (CYP2D6) were found, indicating that none of the five PPIs [including omeprazole, lansoprazole, pantoprazole rameprazole and esomeprazole] inhibited CYP2D6 activity in vitro (IC50 200micM). However, rabeprazole thioether inhibited CYP2D6 activity with a Ki of 12micM in HLM. Drug Interactions ... An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. None None None None in vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. None None Quote: CYP2C19. R- and S-CT were very weak inhibitors, with less than 50% inhibition of S-mephenytoin hydroxylation even at 100micM. R- and S-DCT also were weak inhibitors. R- and S-DDCT were moderate inhibitors, with mean IC50 values of 18.7 and 12.1micM, respectively. Omeprazole was a strong inhibitor of CYP2C19, as was the SSRI fluvoxamine (see Table 2). Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. None None Enzyme system: human liver microsomes NADPH added: yes reaction: 7-ethoxyresoruvin O-deethylation The IC50 for ziprasidone inhibition of this reaction was greater than 100micM None None In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited. None None route of administration: oral study duration: a single 25 mg dose of racemic warfarin either alone or on Day 15 of a 21-day oral dosing regimen of 40 mg citalopram daily. Blood samples for pharmacokinetic analysis were obtained over a 168 h period after warfarin dosing. population: 12 healthy males tested for known CYP450 polymorphisms? no ages: 21 - 32 description: Citalopram produced no change in the pharmacokinetics of (R)- and (S)-warfarin, indicating that citalopram does not alter the metabolism of warfarin mediated via CYP1A2, CYP3A4 and CYP2C9. None None Drug interactions: In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. None None Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. 7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. None None 7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. None None Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None Drug Interactions ... Midazolam: There were no significant differences in the pharmacokinetics of midazolam, a CYP3A4 and CYP3A5 substrate, in subjects receiving 90 mg cinacalcet once daily for 5 days and a single dose of 2 mg midazolam on day 5 as compared to those of subjects receiving 2 mg midazolam alone. This suggests that cinacalcet would not affect the pharmacokinetics of drugs predominantly metabolized by CYP3A4 and CYP3A5. None None Drug Interactions .... Midazolam: There were no significant differences in the pharmacokinetics of midazolam, a CYP3A4 and CYP3A5 substrate, in subjects receiving 90 mg cinacalcet once daily for 5 days and a single dose of 2 mg midazolam on day 5 as compared to those of subjects receiving 2 mg midazolam alone. This suggests that cinacalcet would not affect the pharmacokinetics of drugs predominantly metabolized by CYP3A4 and CYP3A5. None None Drug Interactions ... An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. None None None None Quote: In all systems the positive control inhibitors produced the expected degree of inhibition of their respective index reactions (Table 1). CYP1A2. R- and S-CT and metabolites all were negligible inhibitors of phenacetin O-deethylation, the index reaction for CYP1A2. None of these compounds produced 50% inhibition. The mean IC50 for alpha-naphthoflavone was 0.2micM, and the mean IC50 for fluvoxamine was 0.3micM. CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. None None None None Quote: The IC50 for venlafaxine's inhibition of the reaction was &gt; 1000micM Drug interactions: In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. None None None None in vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. None None Quote: CYP2C9. R-CT, S-CT, R-DCT, and S-DCT were weak inhibitors of CYP2C9, represented by tolbutamide hydroxylation, with less than 50% inhibition produced even at 250micM. R-DDCT and S-DDCT produced a moderate degree of inhibition, with IC50 values of 30.7 (+/-6.3)micM and 25.7 (+/-8.0)micM, respectively. Sulfaphenazole was a strong inhibitor (IC50 1.3micM), and the SSRI fluvoxamine also was a moderately strong inhibitor (IC50 9.4micM). Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Quote: No inhibition was found in microsomal preparations made from human livers with adequate CYP2D6 activity or with expressed CYP2D or with adequate activity of CYPs 1A2, 2A6, 2C9, 2E1, and 3A4. None None Quote: CYP2D6. Only R-DCT had potentially important inhibiting potency versus CYP2D6, represented by dextromethorphan O-demethylation. The mean IC50 was 25.5 (+/-2.1)micM. This is very close to the inhibitory potency of sertraline and is consistent with clinical data suggesting that racemic citalopram and sertraline have comparably weak CYP2D6 inhibitory potency. The SSRI paroxetine was at least an order of magnitude more potent (IC50 2.6micM) than R-DCT as a CYP2D6 inhibitor (see Table 2). Fluoxetine and norfluoxetine (mean IC50 = 2.0 and 2.7micM, respectively) also were strong CYP2D6 inhibitors. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Drug interactions: In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. None None Quote: CYP2D6 Activity. No significant effects on the formation of 1 -hydroxylated bufuralol (CYP2D6) were found, indicating that none of the five PPIs [including omeprazole, lansoprazole, pantoprazole rameprazole and esomeprazole] inhibited CYP2D6 activity in vitro (IC50 200micM). However, rabeprazole thioether inhibited CYP2D6 activity with a Ki of 12micM in HLM. None None Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. None None None None Quote: The IC50 for venlafaxine's inhibition of the reaction was &gt; 1000micM route of administration: oral study duration: single doses of caffeine (200mg NoDoz) on days 1 and 8; venlafaxine 37.5 mg bid days 2-4 and 75 mg bid days 5-8. population:16 healthy volunteers (1 later dropped out); 9 male 7 female tested for known CYP450 polymorphisms? no ages: 21 - 41 description: The treatments did not differ significantly with respect to AUC, C_max, or clearance though there was a small but statistically significant decrease in caffeine half-life None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. None None Enzyme system: human liver microsomes NADPH added: yes reaction: tolbutamide hydroxylation The IC50 for ziprasidone inhibition of this reaction was greater than 100micM None None Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates.Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. None None Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Quote: No inhibition was found in microsomal preparations made from human livers with adequate CYP2D6 activity or with expressed CYP2D or with adequate activity of CYPs 1A2, 2A6, 2C9, 2E1, and 3A4. In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4. None None In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited. None None Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates.Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. None None None None Quote: Mirtazapine reduced the rate of the reaction by much less than 50% at concentrations of 100micM (see Table 3). In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4. None None Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None 7.10 Drugs Metabolized by CYP2C9 Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, although clinical studies have not been performed. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None 7.5 Effect of Atomoxetine on P450 Enzymes Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. None None In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4. None None An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. None None Dextromethorphan Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio. None None Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6. None None Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6. None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. None None Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None None None Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. None None Enzyme system: human liver microsomes NADPH added: yes reaction: S-mephenytoin 4'-hydroxylatoin The IC50 for ziprasidone inhibition of this reaction was greater than 100micM None None Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes. None None Drug Interactions ... An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited. None None None None Quote: CYP3A. CT and metabolites all were very weak or negligible inhibitors of CYP3A, as indicated by triazolam hydroxylation. None of the compounds (at 100micM) produced more than 50% inhibition. Fluvoxamine and nefazodone were moderately strong inhibitors (von Moltke et al., 1996b, 1999c). route of administration: oral study duration: Subjects received triazolam 0.25 mg alone and another 0.25-mg dose after 4 weeks of citalopram 20 mg/day for 1 week, followed by 3 weeks of citalopram 40 mg/day population: 17 (7 men and 10 women) completed the study) tested for known CYP450 polymorphisms? ages: 18 - 31 description: The pharmacokinetics of triazolam and its metabolite alpha-hydroxytriazolam were unchanged by citalopram coadministration. None None 7.19 Drugs Metabolized by Cytochrome P4502D6 In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6. None None None None Quote: CYP2D6. Only R-DCT had potentially important inhibiting potency versus CYP2D6, represented by dextromethorphan O-demethylation. The mean IC50 was 25.5 (+/-2.1)micM. This is very close to the inhibitory potency of sertraline and is consistent with clinical data suggesting that racemic citalopram and sertraline have comparably weak CYP2D6 inhibitory potency. The SSRI paroxetine was at least an order of magnitude more potent (IC50 2.6micM) than R-DCT as a CYP2D6 inhibitor (see Table 2). Fluoxetine and norfluoxetine (mean IC50 = 2.0 and 2.7micM, respectively) also were strong CYP2D6 inhibitors. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None None None Quote: CYP2C19. R- and S-CT were very weak inhibitors, with less than 50% inhibition of S-mephenytoin hydroxylation even at 100micM. R- and S-DCT also were weak inhibitors. R- and S-DDCT were moderate inhibitors, with mean IC50 values of 18.7 and 12.1micM, respectively. Omeprazole was a strong inhibitor of CYP2C19, as was the SSRI fluvoxamine (see Table 2). Drug Interactions ... An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. None None None None Quote: Mirtazapine reduced the rate of the reaction by much less than 50% even at concentrations of 250micM (see Table 3). Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates.Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None None None Quote: CYP2D6 Activity. No significant effects on the formation of 1 -hydroxylated bufuralol (CYP2D6) were found, indicating that none of the five PPIs [including omeprazole, lansoprazole, pantoprazole rameprazole and esomeprazole] inhibited CYP2D6 activity in vitro (IC50 200micM). However, rabeprazole thioether inhibited CYP2D6 activity with a Ki of 12micM in HLM. Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None None None Quote: In all systems the positive control inhibitors produced the expected degree of inhibition of their respective index reactions (Table 1). CYP1A2. R- and S-CT and metabolites all were negligible inhibitors of phenacetin O-deethylation, the index reaction for CYP1A2. None of these compounds produced 50% inhibition. The mean IC50 for alpha-naphthoflavone was 0.2micM, and the mean IC50 for fluvoxamine was 0.3micM. CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. None None None None Quote: The IC50 for venlafaxine's inhibition of the reaction was &gt; 1000micM In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4. None None Enzyme system: human liver microsomes NADPH added: yes reaction: paclitaxel --&gt; 6alpha-OH-paclitaxel &quot;No IC50 values could be determined for rosuvastatin and pravastatin with concentrations up to 100micM&quot; Concentration of pravastatin in vivo based on the largest C_max in label in table 1 of http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1652: 3650ng/1ml x 1g/1e9ng x 1e3ml/1L = .004g/L .004g/L x 1M/853.9g = 4.68micM/L None None None None Quote: CYP2C9. R-CT, S-CT, R-DCT, and S-DCT were weak inhibitors of CYP2C9, represented by tolbutamide hydroxylation, with less than 50% inhibition produced even at 250micM. R-DDCT and S-DDCT produced a moderate degree of inhibition, with IC50 values of 30.7 (+/-6.3)micM and 25.7 (+/-8.0)micM, respectively. Sulfaphenazole was a strong inhibitor (IC50 1.3micM), and the SSRI fluvoxamine also was a moderately strong inhibitor (IC50 9.4micM). In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None None None Quote: Mirtazapine reduced the rate of the reaction by much less than 50% even at concentrations of 250micM (see Table 3). In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Quote: No inhibition was found in microsomal preparations made from human livers with adequate CYP2D6 activity or with expressed CYP2D or with adequate activity of CYPs 1A2, 2A6, 2C9, 2E1, and 3A4. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None Enzyme system: human liver microsomes NADPH added: yes reaction: paclitaxel --&gt; 6alpha-OH-paclitaxel &quot;No IC50 values could be determined for rosuvastatin and pravastatin with concentrations up to 100micM&quot; Concentration of rosuvastatin in vivo based on the C_max from PMID:14667956 of a 10mg dose (small): .188nM/L; according to labeling both peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to rosuvastatin dose. None None 7.5 Effect of Atomoxetine on P450 Enzymes Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. None None 7.5 Effect of Atomoxetine on P450 Enzymes ... CYP2D6 Substrate (e.g., Desipramine) � Coadministration of STRATTERA (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6. None None Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6. None None 7.5 Effect of Atomoxetine on P450 Enzymes Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9. None None Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None None None Quote: Pantoprazole showed a stronger inhibitory effect (Ki 22mM) on midazolam 1'-hydroxylation than omeprazole (Ki 42micM), esomeprazole (Ki 47micM), and rabeprazole (Ki 51micM). The IC50 of lansoprazole was over 200 M. In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes. None None None None Quote: No inhibition was found in microsomal preparations made from human livers with adequate CYP2D6 activity or with expressed CYP2D or with adequate activity of CYPs 1A2, 2A6, 2C9, 2E1, and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. None None Metabolism Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. None None Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates.Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. None None Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. None None In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. None None Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (see Drug Interactions). None None In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. None None None None in vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. None None Quote: Mirtazapine reduced the rate of the reaction by much less than 50% even at concentrations of 250micM (see Table 3). Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6. None None Enzyme system: human liver microsomes NADPH added: yes reaction: omeprazole-5-hydroxylation No k_i observed None None Route of administration: oral polymorphic enzyme: NO study duration: 7 days population: 12 male ages:21-41 description: Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p &gt; 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes. None None specifies A relation between an information content entity and a product that it (directly/indirectly) specifies annotatedAt refers to refers to is a relation between one entity and the entity that it makes reference to. annotatedBy Collection A collection is described as a group; its parts may also be separately described. See http://dublincore.org/documents/dcmi-type-vocabulary/#H7 describes describes is a relation between one entity and another entity that it provides a description (detailed account of)