Association of pharmacokinetic profiles of lenalidomide in human plasma simulated using pharmacokinetic data in humanized-liver mice with liver toxicity detected by human serum albumin RNA.
Association of pharmacokinetic profiles of lenalidomide in human plasma simulated using pharmacokinetic data in humanized-liver mice with liver toxicity detected by human serum albumin RNA.
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DOI：
10.2131/jts.43.369
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Yamazaki H
中科院分区：
文献类型：
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作者：
Murayama N;Suemizu H;Uehara S;Kusama T;Mitsui M;Kamiya Y;Shimizu M;Guengerich FP;Yamazaki H
来那度胺已被证明对沙利度胺敏感的动物物种具有潜在的致畸性。筛选不具有致畸性/毒性（归因于药物代谢和处置，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。研究了口服来那度胺（50 mg/kg）后免疫缺陷对照小鼠和人源化肝小鼠中来那度胺的血浆浓度。人源化肝小鼠中来那度胺的血浆浓度（给药后 1-2 小时）略高于对照小鼠，但显着较高（p < 0.05）。来那度胺给药 24 小时后，在人源化肝小鼠的血液中发现了人白蛋白 mRNA（一种肝脏特异性毒性标记物）。来那度胺的人血浆浓度的模拟是通过对照小鼠和人源化肝小鼠的简化的基于生理学的药代动力学模型或通过对报告的人类数据的直接拟合分析来实现的，根据报告的人类低剂量给药后的来那度胺浓度。结果表明，来那度胺（一种通过在沙利度胺中引入一个芳香族氨基并去除一个酮基而产生的化合物）的药代动力学特征，导致对照小鼠和人源化肝小鼠体内药代动力学的物种差异较小，并且免疫缺陷人源化肝小鼠可以作为高剂量药物开发中人类肝损伤的实验模型动物，并进行血浆中人白蛋白RNA分析。
Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity—attributable to drug metabolism and disposition, but having immunomodulatory properties—is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1–2 h after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0.05). Human albumin mRNA, a liver-specific toxicity marker, was found in the blood of humanized-liver mice 24 h after lenalidomide administration. Simulations of human plasma concentrations of lenalidomide were achieved with simplified physiologically-based pharmacokinetic models in control and humanized-liver mice or by the direct fitting analysis of reported human data, in accordance with reported lenalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of lenalidomide, a compound resulting from introducing one aromatic amino group into thalidomide and removing one keto group, resulted in less species variation in in vivo pharmacokinetics in control and humanized-liver mice and that immunodeficient humanized-liver mice can serve as experimental model animals for human liver injury in drug development at high doses, with human albumin RNA analysis in plasma.