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For successful in vitro-to-in vivo extrapolation of hepatic drug uptake and drug-drug interactions (DDI), it is important to characterize the kinetic properties of the individual transporters involved, their fraction (ft) contribution to hepatic uptake, and their selective inhibitors. Here, we characterized the in vitro transport kinetics of two model drugs, rosuvastatin (RSV) and olmesartan acid (OLM), by rat hepatic organic anion transporting polypeptides (Oatp1a1, 1a4, and 1b2) and identified selective inhibitors of these transporters. [ 3 H]-RSV was transported by Oatp1a1, 1a4, and 1b2, and their Michaelis-Menten constant ( K  m ) values were estimated to be 9.61, 67.2, and 28.1 µ M, respectively. In contrast, [ 3 H]-OLM was transported by only Oatp1b2 ( K  m : 72.8 µ M). Digoxin (IC 50 : 0.107 µ M) and rifamycin SV (IC 50 : 0.140 and 0.088 µ M for RSV and OLM, respectively) were potent and selective inhibitors of Oatp1a4 and 1b2, respectively, and glyburide (100 µ M) completely inhibited all three rat hepatic Oatps. These inhibitors can therefore be used alone and in combination to determine the contribution of each Oatp to hepatic influx. In addition, the magnitude of in vivo inhibition of sinusoidal uptake clearance of RSV by rifampin was well predicted using rifampin IC 50 profiles for each Oatps and RSV ft by each Oatp. This is the first report to 1) detail the transport kinetics of RSV and OLM by rat hepatic Oatps, 2) identify selective inhibitor concentrations of rat Oatps, and 3) demonstrate successful prediction of the magnitude of transporter-mediated in vivo DDI from IC 50 profiles of an inhibitor and ft of a drug by each transporter.

Transport Kinetics, Selective Inhibition, and Successful Prediction of In Vivo Inhibition of Rat Hepatic Organic Anion Transporting Polypeptides