Inhibition of biliary excretion of methotrexate by probenecid in rats: quantitative prediction of interaction from in vitro data.

摘要: This study was designed to establish a strategy predict drug interactions involving biliary excretion. The interaction between methotrexate and probenecid examined as an model since this has already been clinically reported. Coadministration of reduced the clearance in dose-dependent manner rats. inhibition by confirmed vivo both uptake excretion processes across sinusoidal canalicular membranes, respectively. That is, hepatic clearance, assessed integration plot analysis, steady-state defined with respect unbound methotrexate, were presence probenecid. Probenecid inhibited active transport isolated hepatocytes membrane vesicles, confirming at those two membranes. degree found comparable predicted values using constant suggests that each process can be quantitatively estimated from vitro data. We have also proposed method net circulating plasma into bile, being actually vivo. present analysis demonstrates strategic rationale for predicting systems avoid any false negative predictions.