Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.
Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.
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DOI：
10.1080/00498254.2016.1247218
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Yamazaki H
中科院分区：
文献类型：
--
作者：
Shimizu M;Suemizu H;Mitsui M;Shibata N;Guengerich FP;Yamazaki H
泊马度胺已被证明在沙利度胺敏感的动物物种如兔中具有潜在致畸性。筛选没有致畸性/毒性（归因于细胞色素P450酶形成的代谢产物）但具有免疫调节特性的沙利度胺类似物是开发新抗癌药物的战略途径。在本研究中，在对照和人源化肝脏小鼠中研究了泊马度胺、其主要5-羟基化代谢产物及其葡糖苷酸结合物的血浆浓度。泊马度胺（100 mg/kg）经口给药后，人源化肝脏小鼠中7-羟基泊马度胺和5-羟基泊马度胺葡糖苷酸的血浆浓度略高于对照小鼠。根据人体低剂量给药后报告的泊马度胺浓度，在两组小鼠中采用简化的基于生理学的药代动力学模型模拟泊马度胺的人血浆浓度。结果表明，泊马度胺的药代动力学特征在对照小鼠和人源化肝小鼠之间大致相似，并且对照小鼠和人源化肝小鼠在体内介导泊马度胺5-羟基化。在对照组和人源化肝小鼠中，将一个芳香族氨基引入沙利度胺导致体内药代动力学的种属差异较小。
Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity—attributable to metabolites formed by cytochrome P450 enzymes—but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.