This pathway shows the biotransformation of the chemotherapy prodrug irinotecan to form the active metabolite SN-38, an inhibitor of DNA topoisomerase I. SN-38 is primarily metabolized to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Irinotecan is used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. There is large interpatient variability in response to irinotecan, as well as severe side effects such as diarrhea and neutropenia, which might be explained in part by genetic variation in the metabolic enzymes and transporters depicted here. Well-known variants to effect this pathway are the promoter polymorphic repeat in UGT1A1 (UGT1A1*28) and the 1236C>T polymorphism in ABCB1. While UGT1A1*28 genotype has been associated with toxicity, further evidence is needed to describe the roles of ABCB1 variants in toxicity. Source: [http://www.pharmgkb.org/search/pathway/irinotecan/liver.jsp PharmGkb] Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP229 CPTAC Assay Portal] AKA 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)] molecular weight, 558 fd7 d54 cc6 d4c cb7 bc2 ae6 aa1 a33 aa1 a33 ecb ac8 e72 e81 ae6 aa1 a33 12181437 PubMed Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 2002 Gagné JF Montminy V Belanger P Journault K Gaucher G Guillemette C 10815927 PubMed Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 2000 Santos A Zanetta S Cresteil T Deroussent A Pein F Raymond E Vernillet L Risse ML Boige V Gouyette A Vassal G 11602529 PubMed A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4. Drug Metab Dispos 2001 Sai K Kaniwa N Ozawa S Sawada JI 12730278 PubMed Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients. J Pharmacol Exp Ther 2003 Jinno H Saeki M Saito Y Tanaka-Kagawa T Hanioka N Sai K Kaniwa N Ando M Shirao K Minami H Ohtsu A Yoshida T Saijo N Ozawa S Sawada J cancer DOID:162 Disease 15608127 PubMed Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 2005 Nozawa T Minami H Sugiura S Tsuji A Tamai I 14646693 PubMed Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 2003 Sai K Kaniwa N Itoda M Saito Y Hasegawa R Komamura K Ueno K Kamakura S Kitakaze M Shirao K Minami H Ohtsu A Yoshida T Saijo N Kitamura Y Kamatani N Ozawa S Sawada J enterocyte CL:0000584 Cell Type 11990381 PubMed UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002 Iyer L Das S Janisch L Wen M Ramírez, J Karrison T Fleming GF Vokes EE Schilsky RL Ratain MJ 12960109 PubMed Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 2003 Mathijssen RH Marsh S Karlsson MO Xie R Baker SD Verweij J Sparreboom A McLeod HL neutropenia DOID:1227 Disease irinotecan drug pathway PW:0001224 Pathway Ontology diarrhea DOID:13250 Disease 12893990 PubMed UGT pharmacogenomics: implications for cancer risk and cancer therapeutics. Pharmacogenetics 2003 Desai AA Innocenti F Ratain MJ 12810652 PubMed Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin. Cancer Res 2003 Rajendra R Gounder MK Saleem A Schellens JH Ross DD Bates SE Sinko P Rubin EH 10220571 PubMed ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P. Mol Pharmacol 1999 Chen ZS Furukawa T Sumizawa T Ono K Ueda K Seto K Akiyama SI hepatocyte CL:0000182 Cell Type 9466980 PubMed Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998 Iyer L King CD Whitington PF Green MD Roy SK Tephly TR Coffman BL Ratain MJ 10197614 PubMed The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase. Cancer Res 1999 Morton CL Wadkins RM Danks MK Potter PM