TY - JOUR T1 - Prediction and quantification of hepatic transporter-mediated uptake of pitavastatin utilizing a combination of the Relative Activity Factor approach and mechanistic modeling JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.080614 SP - dmd.118.080614 AU - Pallabi Mitra AU - Samantha Weinheimer AU - Meeghan Michalewicz AU - Mitchell E Taub Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/04/17/dmd.118.080614.abstract N2 - Quantification of the fraction transported (ft) by a particular transporter will facilitate more robust estimations of transporter interactions. Using pitavastatin as a model uptake transporter substrate, we investigated the utility of the relative activity factor (RAF) approach and mechanistic modeling, to estimate ft in hepatocytes. Transporters evaluated were OATP1B1, OATP1B3, and NTCP. Transporter expressing HEK293 cells and human hepatocytes were used for determining RAF values, which were then incorporated into the mechanistic model to simulate hepatocyte uptake of pitavastatin over time. There was excellent agreement between simulated and observed hepatocyte uptake of pitavastatin indicating the suitability of this approach for translation of uptake from individual transporter-expressing cells to more holistic in vitro models. Subsequently, ft values were determined. The largest contributor to hepatocyte uptake of pitavastatin was found to be OATP1B1, which correlates with what is known about the in vivo disposition of pitavastatin. The ft values were then used for evaluating in vitro in vivo correlations (IVIVC) of hepatic uptake inhibition with OATP inhibitors rifampicin and cyclosporine. Predictions were compared with previously-reported plasma exposure changes of pitavastatin with these inhibitors. Although hepatic uptake inhibition of pitavastatin was 2-3X under predicted, incorporation of scaling factors (SFs) into RAF values significantly improved the predictive ability. We propose that calibration of hepatocytes with standard transporter substrates and inhibitors would allow for determination of system-specific SFs, which subsequently could be used for refining predictions of clinical DDI potential for NCEs that undergo active hepatic uptake. ER -