title: Quantitative prediction of transporter- and enzyme-mediated clinical drug-drug interactions of organic anion-transporting polypeptide 1B1 substrates using a mechanistic net-effect model.
abstract: Quantitative prediction of complex drug-drug interactions (DDIs) involving hepatic transporters and cytochromes P450 (P450s) is challenging. We evaluated the extent of DDIs of nine victim drugs-which are substrates to organic anion-transporting polypeptide 1B1 and undergo P450 metabolism or biliary elimination-caused by five perpetrator drugs, using in vitro data and the proposed extended net-effect model. Hepatobiliary transport and metabolic clearance estimates were obtained from in vitro studies. Of the total of 62 clinical interaction combinations assessed using the net-effect model, 58 (94%) could be predicted within a 2-fold error, with few false-negative predictions. Model predictive performance improved significantly when in vitro active uptake clearance was corrected to recover in vivo clearance. The basic R-value model yielded only 63% predictions within 2-fold error. This study demonstrates that the interactions involving transporter-enzyme interplay need to be mechanistically assessed for quantitative rationalization and prospective prediction.
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer, Groton, Connecticut manthena.v.varma@pfizer.com.
authors.forename: Manthena V
authors.initials: MV
authors.lastname: Varma
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer, Groton, Connecticut.
authors.forename: Yi-an
authors.initials: YA
authors.lastname: Bi
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer, Groton, Connecticut.
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer, Groton, Connecticut.
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D000959:Antihypertensive Agents; D000960:Hypolipidemic Agents; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System