Physiologically Based Pharmacokinetic Modeling of Bosentan Identifies the Saturable Hepatic Uptake As a Major Contributor to Its Nonlinear Pharmacokinetics
Physiologically Based Pharmacokinetic Modeling of Bosentan Identifies the Saturable Hepatic Uptake As a Major Contributor to Its Nonlinear Pharmacokinetics
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DOI：
10.1124/dmd.117.078972
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发表时间：
2018-05-01
影响因子：
3.9
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
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作者：
Sato, Masanobu;Toshimoto, Kota;Sugiyama, Yuichi
波生坦是肝摄取转运蛋白有机阴离子转运多肽（OATP）的底物，通过细胞色素P450（P450）即CYP 3A 4和CYP 2C 9进行广泛的肝代谢。几项临床研究报告了波生坦剂量与其全身暴露量之间的非线性关系，这可能涉及肝脏中OATP介导的摄取、P450介导的代谢或两者的饱和。然而，非线性波生坦药代动力学的根本原因尚未完全阐明。为了解决这一问题，我们对波生坦以不同剂量静脉给药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，使用体外动力学参数、其他相关参数和比例因子进行PBPK建模分析。作为自上而下的方法，比较了三种不同类型的PBPK模型，这些模型包括肝脏摄取饱和度、代谢饱和度或两者。自下而上方法（模型1和2）的预测得出的波生坦血药浓度-时间曲线及其全身清除率值与临床观察数据不一致。从自上而下的方法（模型3、4、5-1和5-2）来看，仅在结合波生坦的可饱和肝脏摄取时预测准确度最佳。总之，成功建立了波生坦的PBPK模型，不同PBPK模型的比较确定了肝摄取过程的饱和是波生坦非线性药代动力学的主要影响因素。
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 non-linear 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.