RT Journal Article
SR Electronic
T1 Transport Kinetics, Selective Inhibition, and Successful Prediction of In Vivo Inhibition of Rat Hepatic Oatps
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.080770
DO 10.1124/dmd.118.080770
A1 Kazuya Ishida
A1 Mohammed Ullah
A1 Beata Toth
A1 Viktoria Juhasz
A1 Jashvant D Unadkat
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/06/11/dmd.118.080770.abstract
AB For successful in vitro-to-in vivo extrapolation (IVIVE) of hepatic drug uptake and 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. [3H]-RSV was transported by Oatp1a1, 1a4 and 1b2, and their Km values were estimated to be 9.61, 67.2, and 28.1 μM, respectively. In contrast, [3H]-OLM was transported by only Oatp1b2 (Km: 72.8 μM). Digoxin (IC50: 0.107 μM) and rifamycin SV (IC50: 0.140 and 0.088 μM for RSV and OLM, respectively) were potent and selective inhibitors of Oatp1a4 and 1b2, respectively, whilst glyburide (100 μM) 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 IC50 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; 3) demonstrate successful prediction of the magnitude of transporter-mediated in vivo DDI from IC50 profiles of an inhibitor and ft of a drug by each transporter.