PT - JOURNAL ARTICLE AU - Hannah M Jones AU - Hugh A Barton AU - Yurong Lai AU - Yi-an Bi AU - Emi Kimoto AU - Sarah Kempshall AU - Sonya C Tate AU - Ayman El-Kattan AU - Brian Houston AU - Aleksandra Galetin AU - Katherine S Fenner TI - Mechanistic Pharmacokinetic Modelling for the Prediction of Transporter-mediated Disposition in Human from Sandwich Culture Human Hepatocyte Data AID - 10.1124/dmd.111.042994 DP - 2012 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.111.042994 4099 - http://dmd.aspetjournals.org/content/early/2012/02/16/dmd.111.042994.short 4100 - http://dmd.aspetjournals.org/content/early/2012/02/16/dmd.111.042994.full AB - With efforts to reduce CYP450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison to compounds with passively mediated PK. In this study, we have assessed the predictability of human PK for seven organic anion transporting polypeptides (OATP) substrates (pravastatin, cerivastatin, bosentan, fluvastatin, rosuvastatin, valsartan and repaglinide) where clinical intravenous (i.v.) data were available. In vitro data generated from the sandwich culture human hepatocyte (SCHH) system were simultaneously fit to estimate parameters describing both uptake and biliary efflux. Use of scaled active uptake, passive distribution and biliary efflux parameters as inputs into a PBPK model resulted in the over-prediction of exposure for all seven drugs investigated, with the exception of pravastatin. Therefore, fitting of in vivo data for each individual drug in the dataset was performed to establish empirical scaling factors to accurately capture their plasma concentration-time profiles. Overall, active uptake and biliary efflux were under- and over-predicted, leading to average empirical scaling factors of 58 and 0.061, respectively; passive diffusion required no scaling factor. This study illustrates the mechanistic and model-driven application of in vitro uptake and efflux data for human PK prediction for OATP substrates. A particular advantage is the ability to capture the multiphasic plasma concentration-time profiles for such compounds using only pre-clinical data. A prediction strategy for novel OATP substrates is discussed.