Yamazaki Hiroshi, Suemizu Hiroshi, Mitsui Marina, Shimizu Makiko, Guengerich F Peter
Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
Central Institute for Experimental Animals , Kawasaki-ku, Kawasaki 210-0821, Japan.
Chem Res Toxicol. 2016 Dec 19;29(12):1903-1911. doi: 10.1021/acs.chemrestox.6b00136. Epub 2016 Jul 5.
Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolically activated C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans.
药物氧化活性存在种属差异，主要由细胞色素P450（P450）酶介导。为克服种属外推问题，含有人类P450 3A簇的转基因小鼠或移植了人类肝细胞的嵌合小鼠已被引入人类毒理学研究领域。在本综述中，从邻苯二甲酸酯和双酚A的胆汁/尿液排泄以及人类鸡尾酒探针药物咖啡因、华法林、奥美拉唑、美托洛尔和咪达唑仑的血浆清除率方面，总结了嵌合小鼠中人性化肝脏介导的药物代谢和处置情况。根据报告的临床沙利度胺浓度，利用基于嵌合小鼠获得的数据的简化生理药代动力学模型，可以模拟致畸剂沙利度胺及其人类代谢物的人体血浆浓度。此外，通过加速器质谱分析法可以分析人性化肝脏小鼠中代谢活化的C类候选药物和肝毒性药物的体内非特异性肝蛋白结合参数，这对于人类预测很有用。
