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"EffluxInterstitialToPlasma" } ] }, { "Type": "Enzyme", "Species": "Human", "Molecule": "UGT2B7", "Category": "Healthy", "Parameters": [ { "Path": "Organism|Gonads|Intracellular|UGT2B7|Relative expression", "Value": 0.00094468085106 }, { "Path": "Organism|LargeIntestine|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|LargeIntestine|Mucosa|Caecum|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|LargeIntestine|Mucosa|ColonAscendens|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|LargeIntestine|Mucosa|ColonDescendens|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|LargeIntestine|Mucosa|ColonSigmoid|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|LargeIntestine|Mucosa|ColonTransversum|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|LargeIntestine|Mucosa|Rectum|Intracellular|UGT2B7|Relative expression", "Value": 0.0049787234043 }, { "Path": "Organism|Liver|Pericentral|Intracellular|UGT2B7|Relative expression", "Value": 1.0 }, { "Path": "Organism|Liver|Periportal|Intracellular|UGT2B7|Relative expression", "Value": 1.0 }, { "Path": "Organism|Pancreas|Intracellular|UGT2B7|Relative expression", "Value": 0.0354468085 }, { "Path": "Organism|SmallIntestine|Intracellular|UGT2B7|Relative expression", "Value": 0.5361702128 }, { "Path": "Organism|SmallIntestine|Mucosa|Duodenum|Intracellular|UGT2B7|Relative expression", "Value": 0.5361702128 }, { "Path": "Organism|SmallIntestine|Mucosa|LowerIleum|Intracellular|UGT2B7|Relative expression", "Value": 0.5361702128 }, { "Path": "Organism|SmallIntestine|Mucosa|LowerJejunum|Intracellular|UGT2B7|Relative expression", "Value": 0.5361702128 }, { "Path": "Organism|SmallIntestine|Mucosa|UpperIleum|Intracellular|UGT2B7|Relative expression", "Value": 0.5361702128 }, { "Path": "Organism|SmallIntestine|Mucosa|UpperJejunum|Intracellular|UGT2B7|Relative expression", "Value": 0.5361702128 }, { "Path": "UGT2B7|Reference concentration", "Value": 3.372, "Unit": "µmol/l", "ValueOrigin": { "Source": "Publication", "Description": "Ohtsuki et al. 2011" } }, { "Path": "UGT2B7|t1/2 (intestine)", "Value": 1380.0, "Unit": "min" }, { "Path": "UGT2B7|t1/2 (liver)", "Value": 2160.0, "Unit": "min" } ], "Localization": "Intracellular, BloodCellsIntracellular, VascEndosome", "Ontogeny": { "Name": "UGT2B7" } }, { "Type": "Enzyme", "Species": "Human", "Molecule": "Hepatic-CYP", "Category": "Healthy", "Parameters": [ { "Path": "Hepatic-CYP|Reference concentration", "Value": 1.0, "Unit": "µmol/l" }, { "Path": "Hepatic-CYP|t1/2 (intestine)", "Value": 1380.0, "Unit": "min" }, { "Path": "Hepatic-CYP|t1/2 (liver)", "Value": 2160.0, "Unit": "min" }, { "Path": "Organism|Liver|Pericentral|Intracellular|Hepatic-CYP|Relative expression", "Value": 1.0 }, { "Path": "Organism|Liver|Periportal|Intracellular|Hepatic-CYP|Relative expression", "Value": 1.0 } ], "Localization": "Intracellular, BloodCellsIntracellular, VascEndosome" } ], "Individuals": [ { "Name": "Standard_Adult_UGT", "Seed": 965997659, "OriginData": { "CalculationMethods": [ "SurfaceAreaPlsInt_VAR1", "Body surface area - Mosteller" ], "Species": "Human", "Population": "European_ICRP_2002", "Gender": "MALE", "Age": { "Value": 30.0, "Unit": "year(s)" } }, "Parameters": [ { "Path": "Organism|Liver|EHC continuous fraction", "Value": 1.0, "ValueOrigin": { "Source": "Unknown" } }, { "Path": "Organism|Lumen|Caecum|Effective surface area enhancement factor", "Value": 0.3067717772, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'Parameter Identification-17457' on 2019-08-02 13:57" } }, { "Path": "Organism|Lumen|ColonAscendens|Effective surface area enhancement factor", "Value": 0.4260719128, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'Parameter Identification-17457' on 2019-08-02 13:57" } }, { "Path": "Organism|Lumen|ColonDescendens|Effective surface area enhancement factor", "Value": 0.4260719128, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'Parameter Identification-17457' on 2019-08-02 13:57" } }, { "Path": "Organism|Lumen|ColonSigmoid|Effective surface area enhancement factor", "Value": 0.4260719128, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'Parameter Identification-17457' on 2019-08-02 13:57" } }, { "Path": "Organism|Lumen|ColonTransversum|Effective surface area enhancement factor", "Value": 0.4260719128, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'Parameter Identification-17457' on 2019-08-02 13:57" } }, { "Path": "Organism|Lumen|Rectum|Effective surface area enhancement factor", "Value": 0.6067264038, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'Parameter Identification-17457' on 2019-08-02 13:57" } } ], "ExpressionProfiles": [ "CYP3A4|Human|Healthy", "CYP1A1|Human|Healthy", "UGT1A1|Human|Healthy", "UGT1A9|Human|Healthy", "Cleavage-protein|Human|Healthy", "ABCG2|Human|Healthy", "ABCB1|Human|Healthy", "M-1 TS|Human|Healthy", "UGT2B7|Human|Healthy", "Hepatic-CYP|Human|Healthy" ] } ], "Compounds": [ { "Name": "Dapagliflozin", "IsSmallMolecule": true, "PlasmaProteinBindingPartner": "Albumin", "Lipophilicity": [ { "Name": "Optimized", "Parameters": [ { "Name": "Lipophilicity", "Value": 2.6719093089, "Unit": "Log Units", "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'PI full (perm)' 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updated from 'PI full (perm)' on 2019-08-23 15:34" } } ] } ], "Permeability": [ { "Name": "Optimized", "Parameters": [ { "Name": "Permeability", "Value": 0.00037527645658, "Unit": "cm/min", "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'PI full (perm)' on 2019-08-23 15:34" } } ] } ], "PkaTypes": [ { "Type": "Acid", "Pka": 12.75, "ValueOrigin": { "Source": "Database", "Description": "DrugBank DB06292" } } ], "Processes": [ { "InternalName": "MetabolizationSpecific_FirstOrder", "DataSource": "Optimized", "Molecule": "UGT1A9", "Metabolite": "Dapagliflozin-3-O-glucuronide", "Parameters": [ { "Name": "Enzyme concentration", "Value": 1.0, "Unit": "µmol/l" }, { "Name": "Specific clearance", "Value": 0.0, "Unit": "1/min" }, { "Name": "CLspec/[Enzyme]", "Value": 0.399443557, "Unit": "l/µmol/min", "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'PI full (perm)' on 2019-08-23 15:34" } } ] }, { "InternalName": "MetabolizationSpecific_FirstOrder", "DataSource": "Optimized", "Molecule": "UGT2B7", "Metabolite": "Dapagliflozin-2-O-glucuronide", "Parameters": [ { "Name": "Enzyme concentration", "Value": 1.0, "Unit": "µmol/l" }, { "Name": "Specific clearance", "Value": 0.0, "Unit": "1/min" }, { "Name": "CLspec/[Enzyme]", "Value": 0.0066043366201, "Unit": "l/µmol/min", "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'PI full (perm)' on 2019-08-23 15:34" } } ] }, { "InternalName": "GlomerularFiltration", "DataSource": "assumed", "Species": "Human", "Parameters": [ { "Name": "GFR fraction", "Value": 0.7899801465, "ValueOrigin": { "Source": "ParameterIdentification", "Method": "ParameterIdentification", "Description": "Value updated from 'PI full (perm)' on 2019-08-23 15:34" } } ] }, { "InternalName": "MetabolizationSpecific_FirstOrder", "DataSource": 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(n=7)" ] }, { "Name": "Chang 2015", "Classifiables": [ "Chang 2015 - Study 1 Treatment A (single oral doses) - Dapagliflozin - PO - 5 mg - Plasma - agg. (n=36)", "Chang 2015 - Study 2 Treatment A (single oral doses) - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=36)" ] }, { "Name": "Imamura 2013", "Classifiables": [ "Imamura 2013 - Control (Perpetrator Placebo) - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=22)" ] }, { "Name": "Kasichayanula 2011a", "Classifiables": [ "Kasichayanula 2011a - fed - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=14)", "Kasichayanula 2011a - fasted - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=14)" ] }, { "Name": "Kasichayanula 2011b", "Classifiables": [ "Kasichayanula 2011b - Study 3: 20 mg Control (Perpetrator Placebo) - Dapagliflozin - PO - 20 mg - Plasma - agg. (n=18)", "Kasichayanula 2011b - Study 2: 20 mg Control (Perpetrator Placebo) - Dapagliflozin - PO - 20 mg - Plasma - agg. (n=18)", "Kasichayanula 2011b - Study 1: 50 mg Control (Perpetrator Placebo) - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=24)" ] }, { "Name": "Kasichayanula 2012", "Classifiables": [ "Kasichayanula 2012 - Study 1: Control (Perpetrator Placebo) - Dapagliflozin - PO - 20 mg - Plasma - agg. (n=24)" ] }, { "Name": "Kasichayanula 2013a", "Classifiables": [ "Kasichayanula 2013a - Study 2: Control (Perpetrator Placebo) - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=16)", "Kasichayanula 2013a - Study 1: Control (Perpetrator Placebo) - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=14)" ] }, { "Name": "Kasichayanula 2013b", "Classifiables": [ "Kasichayanula 2013b - T2DM with severe renal impairment - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=4)", "Kasichayanula 2013b - T2DM with moderate renal impairment - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=8)", "Kasichayanula 2013b - T2DM with mild renal impairment - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=8)", "Kasichayanula 2013b - T2DM with normal kidney function - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=12)", "Kasichayanula 2013b - Healthy subjects with normal kidney function - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=8)" ] }, { "Name": "Vakkalagadda 2016", "Classifiables": [ "Vakkalagadda 2016 - Dapagliflozin - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=42)" ] }, { "Name": "DeFronzo 2013", "Classifiables": [ "DeFronzo 2013 - Healthy Subjects - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=12)" ] }, { "Name": "Kasichayanula 2011c", "Classifiables": [ "Kasichayanula 2011c - Healthy Volunteers - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=6)" ] }, { "Name": "Komoroski 2009", "Classifications": [ { "Name": "Urine", "Classifiables": [ "Komoroski 2009 - SAD 2.5 mg (Urine) - Dapagliflozin - PO - 2.5 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 5 mg (Urine) - Dapagliflozin - PO - 5 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 10 mg (Urine) - Dapagliflozin - PO - 10 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 20 mg (Urine) - Dapagliflozin - PO - 20 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 50 mg (Urine) - Dapagliflozin - PO - 50 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 100 mg (Urine) - Dapagliflozin - PO - 100 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 250 mg fasted (Urine) - Dapagliflozin - PO - 250 mg - Urine - agg. (n=6)", "Komoroski 2009 - SAD 500 mg (Urine) - Dapagliflozin - PO - 500 mg - Urine - agg. (n=6)" ] }, { "Name": "Plasma", "Classifications": [ { "Name": "MAD", "Classifiables": [ "Komoroski 2009 - MAD 2.5 mg (day 1) - Dapagliflozin - PO - 2.5 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 10 mg (day 1) - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 20 mg (day 1) - Dapagliflozin - PO - 20 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 50 mg (day 1) - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 100 mg (day 1) - Dapagliflozin - PO - 100 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 2.5 mg (day 7 and day 14) - Dapagliflozin - PO - 2.5 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 10 mg (day 7 and day 14) - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 20 mg (day 7 and day 14) - Dapagliflozin - PO - 20 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 50 mg (day 7 and day 14) - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=6)", "Komoroski 2009 - MAD 100 mg (day 7 and day 14) - Dapagliflozin - PO - 100 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD", "Classifications": [ { "Name": "SAD 2.5 mg", "Classifiables": [ "Komoroski 2009 - SAD 2.5 mg - Dapagliflozin - PO - 2.5 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 5 mg", "Classifiables": [ "Komoroski 2009 - SAD 5 mg - Dapagliflozin - PO - 5 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 10 mg", "Classifiables": [ "Komoroski 2009 - SAD 10 mg - Dapagliflozin - PO - 10 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 20 mg", "Classifiables": [ "Komoroski 2009 - SAD 20 mg - Dapagliflozin - PO - 20 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 50 mg", "Classifiables": [ "Komoroski 2009 - SAD 50 mg - Dapagliflozin - PO - 50 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 100 mg", "Classifiables": [ "Komoroski 2009 - SAD 100 mg - Dapagliflozin - PO - 100 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 250 mg fasted", "Classifiables": [ "Komoroski 2009 - SAD 250 mg fasted - Dapagliflozin - PO - 250 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 500 mg", "Classifiables": [ "Komoroski 2009 - SAD 500 mg - Dapagliflozin - PO - 500 mg - Plasma - agg. (n=6)" ] }, { "Name": "SAD 250 mg fed", "Classifiables": [ "Komoroski 2009 - SAD 250 mg fed - Dapagliflozin - PO - 250 mg - Plasma - agg. (n=6)" ] } ] } ] } ] }, { "Name": "Kasichayanula 2008", "Classifiables": [ "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin Feces - Dapagliflozin - PO - 50 mg - Feces - agg. (n=6)", "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin Urine - Dapagliflozin - PO - 50 mg - Urine - agg. (n=6)", "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin oxid Metab - Dapagliflozin oxidative metabolites - PO - 50 mg - Fraction - agg. (n=6)", "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin 2OG Gluc - Dapagliflozin-2-O-glucuronide - PO - 50 mg - Fraction - agg. (n=6)", "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin 3OG Gluc - Dapagliflozin-3-O-glucuronide - PO - 50 mg - Fraction - agg. (n=6)", "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin 3OG Gluc (incl. unchanged feces exret.) - Dapagliflozin-3-O-glucuronide - PO - 50 mg - Fraction - agg. (n=6)", "Kasichayanula 2008 - Mass Balance of 14C-dapagliflozin 2OG Gluc (incl. unchanged feces exret.) - Dapagliflozin-2-O-glucuronide - PO - 50 mg - Fraction - agg. (n=6)" ] } ], "SimulationClassifications": [ { "Name": "model building", "Classifiables": [ "IV 0.08 mg (perm)", "PO SD 10 mg (perm)", "PO SD 50 mg (perm)", "PO SD 2.5 mg (perm)", "PO SD 5 mg (perm)", "PO SD 20 mg (perm)", "PO SD 100 mg (perm)", "PO SD 250 mg (perm)", "PO SD 500 mg (perm)" ] }, { "Name": "model verification", "Classifications": [ { "Name": "multiple dose", "Classifiables": [ "PO MD 10 mg (perm)", "PO MD 100 mg (perm)", "PO MD 2.5 mg (perm)", "PO MD 20 mg (perm)", "PO MD 50 mg (perm)" ] }, { "Name": "IC tablet", "Classifiables": [ "PO SD 5 mg IC tablet (Chang 2015) (perm)", "PO SD 10 mg IC tablet (Chang 2015) (perm)" ] }, { "Name": "fed state", "Classifiables": [ "PO SD 250 mg fed (perm)" ] } ] } ], "ParameterIdentificationClassifications": [ { "Name": "_tests", "Classifiables": [ "PI full (perm) (fe unchanged)", "PI [-logP] (perm)", "PI [-Solub] (perm)", "PI full (perm) MSV" ] } ] }