TY - JOUR T1 - Successful Prediction of In Vivo Hepatobiliary Clearances and Hepatic Concentrations of Rosuvastatin Using Sandwich-Cultured Rat Hepatocytes, Transporter-Expressing Cell Lines, and Quantitative Proteomics JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 66 LP - 74 DO - 10.1124/dmd.117.076539 VL - 46 IS - 1 AU - Kazuya Ishida AU - Mohammed Ullah AU - Beáta Tóth AU - Viktoria Juhasz AU - Jashvant D. Unadkat Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/46/1/66.abstract N2 - We determined whether in vivo transporter-mediated hepatobiliary clearance (CL) and hepatic concentrations of rosuvastatin (RSV) in the rat could be predicted by transport activity in sandwich-cultured rat hepatocytes (SCRHs) and/or transporter-expressing cell lines scaled by differences in transporter protein expression between SCRHs, cell lines, and rat liver. The predicted hepatobiliary CLs and hepatic concentrations of RSV were compared with our previously published positron emission tomography imaging data. Sinusoidal uptake CL () and efflux (canalicular and sinusoidal) CLs of [3H]-RSV in SCRHs were evaluated in the presence and absence of Ca2+ and in the absence and presence of 1 mM unlabeled RSV (to estimate passive diffusion CL). of RSV into cells expressing organic anion transporting polypeptide (Oatp) 1a1, 1a4, and 1b2 was also determined. Protein expression of Oatps in SCRHs and Oatp-expressing cells was quantified by liquid chromatography tandem mass spectrometry. SCRHs well predicted the in vivo RSV sinusoidal and canalicular efflux CLs but significantly underestimated in vivo . Oatp expression in SCRHs was significantly lower than that in the rat liver. , based on RSV into Oatp-expressing cells (active transport) plus passive diffusion CL in SCRHs, scaled by the difference in protein expression in Oatp cells versus SCRH versus rat liver, was within 2-fold of that observed in SCRHs or in vivo. In vivo hepatic RSV concentrations were well predicted by Oatp-expressing cells after correcting for Oatp protein expression. This is the first demonstration of the successful prediction of in vivo hepatobiliary CLs and hepatic concentrations of RSV using transporter-expressing cells and SCRHs. ER -