Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice.
Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice.
复制标题
DOI：
10.1007/s00280-016-3018-6
复制
发表时间：
2016-05
影响因子：
3
通讯作者：
Panetta JC
中科院分区：
文献类型：
--
作者：
Edginton AN;Zimmerman EI;Vasilyeva A;Baker SD;Panetta JC
本研究使用不确定性和敏感性分析来评估小鼠体内索拉非尼及其两种主要代谢物索拉非尼葡萄糖醛酸和索拉非尼 N-氧化物复杂机制的生理药代动力学 (PBPK) 模型。开发了索拉非尼及其两种主要代谢物的 PBPK 模型来解释小鼠体内的分布。它包括相关的流入（Oatp）和流出（Abcc2 和 Abcc3）转运蛋白、肝代谢酶（CYP3A4 和 UGT1A9）以及肠道 β-葡萄糖醛酸酶。药物特异性过程的参数化基于体外、离体和计算机数据以及来自单个和多个转运蛋白敲除小鼠的血浆和肝脏药代动力学数据。不确定性分析表明，模型结构和参数值可以解释观察到的药代动力学数据的变异性。全局敏感性分析证明了代谢酶对索拉非尼和代谢物处置的全局影响以及转运蛋白对其各自底物暴露的局部影响。此外，通过假设检验，该模型支持流入转运蛋白 Oatp 是索拉非尼的弱底物和索拉非尼葡萄糖醛酸苷的强底物，并且流出转运蛋白 Abcc2 并不是 Abcc2 敲除小鼠中唯一受影响的转运蛋白。为了解释异常高的人类药代动力学变异性及其与暴露依赖性剂量限制毒性的关系，将小鼠模型转化为人类，需要描述这些过程对处置的重要性。
This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice. A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knock-out mice. Uncertainty analysis demonstrated that the model structure and parameter values could explain the observed variability in the pharmacokinetic data. Global sensitivity analysis demonstrated the global effects of metabolizing enzymes on sorafenib and metabolite disposition and the local effects of transporters on their respective substrate exposures. In addition, though hypothesis testing, the model supported that the influx transporter Oatp is a weak substrate for sorafenib and a strong substrate for sorafenib glucuronide and that the efflux transporter Abcc2 is not the only transporter affected in the Abcc2 knock-out mouse. Translation of the mouse model to humans for the purpose of explaining exceptionally high human pharmacokinetic variability and its relationship with exposure dependent dose-limiting toxicities will require delineation of the importance of these processes on disposition.