TY - JOUR T1 - Physiologically Based Pharmacokinetic Modeling of Bosentan Identifies the Saturable Hepatic Uptake as A Major Contributor to Its Nonlinear Pharmacokinetics JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.078972 SP - dmd.117.078972 AU - Masanobu Sato AU - Kota Toshimoto AU - Atsuko Tomaru AU - Takashi Yoshikado AU - Yuta Tanaka AU - Akihiro Hisaka AU - Wooin Lee AU - Yuichi Sugiyama Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/02/23/dmd.117.078972.abstract N2 - Bosentan is a substrate of hepatic uptake transporter organic anion transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (CYPs), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, CYP-mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated. To address this, we performed physiologically based pharmacokinetic (PBPK) modeling analyses for bosentan after its iv administration at different doses. As a bottom-up approach, PBPK modeling analyses were performed using in vitro kinetic parameters, other relevant parameters and scaling factors. As top-down approaches, three different types of PBPK models that incorporate the saturation of hepatic uptake, metabolism or both were compared. The prediction from the bottom-up approach (Models 1 and 2) yielded the blood bosentan concentration-time profiles and its systemic clearance values that are not in good agreement with the clinically observed data. From top-down approaches (Models 3, 4, 5-1 and 5-2), the prediction accuracy was best only with the incorporation of the saturable hepatic uptake for bosentan. Taken together, the PBPK models for bosentan were successfully established and comparison of different PBPK models identified the saturation of the hepatic uptake process as a major contributing factor for the nonlinear pharmacokinetics of bosentan. ER -