Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan.
Eur J Pharm Sci. 2021 Jun 1;161:105807. doi: 10.1016/j.ejps.2021.105807. Epub 2021 Mar 17.
The cynomolgus monkey is a nonhuman primate that is often used for pharmacokinetic and toxicokinetic studies of new chemical entities. Species differences in drug metabolism are obstacles for the extrapolation of animal data to humans. This study aimed to characterize hydrolase activities for typical compounds by cynomolgus monkey liver microsomes and recombinant monkey carboxylesterases (CES1 and CES2) and arylacetamide deacetylase (AADAC) compared with the activities in humans. To estimate the contribution of each hydrolase, the ratios of the expression level of each hydrolase in the liver microsomes and recombinant systems were used. For almost all of the tested human CES1 substrates, hydrolase activities in cynomolgus monkey liver microsomes tended to be lower than those in human liver microsomes, and recombinant cynomolgus monkey CES1 showed catalytic activity, but not for all substrates. For human CES2 substrates, hydrolase activities in cynomolgus monkey liver were higher than those in human liver microsomes, and recombinant monkey CES2 was responsible for their hydrolysis. Among human AADAC substrates, phenacetin was mainly hydrolyzed by monkey AADAC, whereas indiplon and ketoconazole were hydrolyzed by AADAC and other unknown enzymes. Flutamide was hydrolyzed by monkey CES2, not by AADAC. Rifamycins were hardly hydrolyzed in monkey liver microsomes. In conclusion, this study characterized the hydrolase activities of cynomolgus monkeys compared with those in humans. The findings would be helpful for pharmacokinetic or toxicokinetic studies of new chemical entities whose main metabolic pathway is hydrolysis.
食蟹猴是一种常用于新化学实体的药代动力学和毒代动力学研究的非人灵长类动物。药物代谢的种属差异是将动物数据外推至人类的障碍。本研究旨在通过食蟹猴肝微粒体和重组猴羧酸酯酶（CES1 和 CES2）和芳基乙酰胺脱乙酰酶（AADAC）比较，来表征典型化合物的水解酶活性，并与人类进行比较。为了估计每种水解酶的贡献，使用肝微粒体和重组系统中每种水解酶的表达水平的比值。对于几乎所有测试的人类 CES1 底物，食蟹猴肝微粒体中的水解酶活性往往低于人类肝微粒体中的活性，重组食蟹猴 CES1 表现出催化活性，但不是针对所有底物。对于人类 CES2 底物，食蟹猴肝中的水解酶活性高于人类肝微粒体中的活性，重组猴 CES2 负责其水解。在人类 AADAC 底物中，扑热息痛主要由猴 AADAC 水解，而吲哚普仑和酮康唑则由 AADAC 和其他未知酶水解。氟他胺由猴 CES2 水解，不由 AADAC 水解。利福平类在猴肝微粒体中几乎不水解。总之，本研究比较了食蟹猴与人类的水解酶活性。这些发现将有助于主要代谢途径为水解的新化学实体的药代动力学或毒代动力学研究。
