Integrated approach of in vivo and in vitro for evaluation of the involvement of hepatic uptake organic anion transporters in the drug disposition in rats using rifampicin as an inhibitor

Integrated approach of in vivo and in vitro for evaluation of the involvement of hepatic uptake organic anion transporters in the drug disposition in rats using rifampicin as an inhibitor Abbreviations Cyp: cytochrome 450 Oatp: organic anion transporting polypeptide OAT: organic anion transporter DDI: drug-drug interactions NCE: new chemical entity SD: Sprague-Dawley LC/MS/MS: liquid chromatography/tandem mass spectrometry Statin: HMG-CoA reductase inhibitor BSP: bromosulphophthalein ABT: 1-aminobenzotriazole CL int : intrinsic clearance CL tot,p : total body clearance based on plasma concentration CL renal,p : renal clearance based on plasma concentration This article has not been copyedited and formatted. The final version may differ from this version. DMD#51052 3 CL h,p : hepatic clearance based on plasma concentration CL h,B : hepatic clearance based on blood concentration CL int,media-loss assay : intrinsic clearance in media-loss assay CL int,metabolic stability assay : intrinsic clearance in metabolic stability assay CL int,hepatocyte uptake : intrinsic clearance in hepatocyte uptake assay CL int,vivo : intrinsic clearance in vivo T 1/2 : terminal half-life X urine : amount of drug into urine Vd ss : apparent volume of disposition at equilibrium MRT: mean residence time AUC p : Area under the plasma concentration curve R B : blood-to-plasma concentration ratio f B : unbound fraction in blood afe: average fold error This article has not been copyedited and formatted. The final version may differ from this version. Abstract Cumulative studies describe the importance of drug transporters as one of the key determinants of pharmacokinetics that necessitate investigation and assessment of the involvement of drug transporters in drug discovery and development. The present study investigated an integrated in vivo and in vitro approach to determine the involvement of organic anion transporting polypeptides (Oatps) in the disposition of drugs in rats using rifampicin as an inhibitor. When bromosulfophthalein (BSP) and HMG-CoA reductase inhibitors (statins), which were used as model substrates for Oatps, were administered intravenously (3 and 1 mg/kg, respectively) to rats pretreated with rifampicin orally (30 mg/kg), the total plasma clearance of BSP and statins was attenuated compared to that in control rats, suggesting the involvement of Oatps in the disposition of these drugs in vivo. On the other hand, the pharmacokinetics of midazolam, used as a model substrate of Cyp3a, was unchanged between control rats and rifampicin-pretreated rats. The involvement of Oatps in the disposition of statins observed in vivo was further clarified by employing an in …