title: Transporter-mediated drug--drug interactions involving OATP substrates: predictions based on in vitro inhibition studies.
abstract: Transporter-mediated drug–drug interactions (DDIs) are among the most important of the clinically relevant pharmacokinetic DDIs. We investigated the validity of a static prediction of area under the plasma concentration-time curve (AUC) ratios (AUCRs; AUC(with inhibitor)/AUC(control) using in vitro inhibition profiles, and selected the types of assumptions that improved the prediction accuracy with minimizing false-negative predictions. We used data from 58 DDI studies involving 12 substrates of hepatic organic anion–transporting polypeptides (OATPs). With original assumptions regarding the maximal increase in intestinal availability, maximum unbound concentration at the inlet to the liver, and inhibition of only the hepatic uptake process, the predicted AUCRs were comparable to those reported within a two/threefold error margin in 44/52 studies, whereas in 16 studies, the predictions were judged to be falsenegatives. When the inhibitory effects on both hepatic uptake and efflux/metabolisms were considered, the overall prediction accuracy became worse, although the false-negative prediction decreased to 11 studies. This illustrates that if appropriate assumptions are selected, unnecessary clinical DDI studies can be reasonably avoided.
authors.affiliation: Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Maeda
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000201:enzymology / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D004798:Enzymes / Q000378:metabolism; D005544:Forecasting; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D010599:Pharmacokinetics
chemical_list: D004798:Enzymes; D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System