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The hepatic organic anion transporting polypeptides (OATPs)influencethe pharmacokinetics of several drug classes and are involved in manyclinical drug–drug interactions. Predicting potential interactionswith OATPs is, therefore, of value. Here, we developed in vitro andin silico models for identification and prediction of specific andgeneral inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transportactivity (MTA) of each OATP in human liver was predicted from transportkinetics and protein quantification. We then used MTA to predict theeffects of a subset of inhibitors on atorvastatin uptake in vivo.Using a data set of 225 drug-like compounds, 91 OATP inhibitors wereidentified. In silico models indicated that lipophilicity and polarsurface area are key molecular features of OATP inhibition. MTA predictionsidentified OATP1B1 and OATP1B3 as major determinants of atorvastatinuptake in vivo. The relative contributions to overall hepatic uptakevaried with isoform specificities of the inhibitors. [ABSTRACT FROM AUTHOR]