Advanced Review with Electronic Data Promotion Group, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan (M.S.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (K.T., A.T., T.Y., Y.S.); DMPK Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan (Y.T); Graduate School and Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan (A.H.); and College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
Advanced Review with Electronic Data Promotion Group, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan (M.S.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan (K.T., A.T., T.Y., Y.S.); DMPK Research Laboratory, Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan (Y.T); Graduate School and Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan (A.H.); and College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.)
Drug Metab Dispos. 2018 May;46(5):740-748. doi: 10.1124/dmd.117.078972. Epub 2018 Feb 23.
Bosentan is a substrate of hepatic uptake transporter organic anion-transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (P450), 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, P450-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 intravenous 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 blood bosentan concentration-time profiles and their systemic clearance values that were 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 the comparison of different PBPK models identified the saturation of the hepatic uptake process as a major contributing factor for the nonlinear pharmacokinetics of bosentan.
波生坦是肝脏摄取转运体有机阴离子转运多肽（OATPs）的底物，通过细胞色素 P450（CYP），主要是 CYP3A4 和 CYP2C9 发生广泛的肝代谢。几项临床研究报告称，波生坦剂量与其全身暴露之间存在非线性关系，这可能涉及 OATP 介导的摄取、P450 介导的代谢或两者在肝脏中的饱和。然而，波生坦药代动力学非线性的根本原因尚未完全阐明。为了解决这个问题，我们在不同剂量下静脉给予波生坦后进行了基于生理学的药代动力学（PBPK）建模分析。作为自下而上的方法，PBPK 建模分析使用了体外动力学参数、其他相关参数和缩放因子。作为自上而下的方法，比较了三种不同类型的 PBPK 模型，这些模型都包含了肝脏摄取、代谢或两者的饱和。自下而上方法（模型 1 和 2）的预测得出的血波生坦浓度-时间曲线及其全身清除率值与临床观察数据不一致。自上而下的方法（模型 3、4、5-1 和 5-2）中，仅当纳入波生坦的可饱和肝摄取时，预测准确性最佳。综上所述，成功建立了波生坦的 PBPK 模型，不同 PBPK 模型的比较确定了肝脏摄取过程的饱和是波生坦非线性药代动力学的主要因素。
