Honda Shiori, Fukami Tatsuki, Hirosawa Keiya, Tsujiguchi Takuya, Zhang Yongjie, Nakano Masataka, Uehara Shotaro, Uno Yasuhiro, Yamazaki Hiroshi, Nakajima Miki
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (S.H., T.F., K.H., T.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Y.Z., Ma.N., Mi.N.), Kanazawa University, Kanazawa, Japan; Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (Y.Z.); Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan (S.U., H.Y.); Central Institute for Experimental Animals, Kawasaki, Japan (S.U.); Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (Y.U.); and Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (Y.U.).
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (S.H., T.F., K.H., T.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Y.Z., Ma.N., Mi.N.), Kanazawa University, Kanazawa, Japan; Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China (Y.Z.); Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan (S.U., H.Y.); Central Institute for Experimental Animals, Kawasaki, Japan (S.U.); Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan (Y.U.); and Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan (Y.U.)
Drug Metab Dispos. 2021 Sep;49(9):718-728. doi: 10.1124/dmd.121.000513. Epub 2021 Jun 16.
For drug development, species differences in drug-metabolism reactions present obstacles for predicting pharmacokinetics in humans. We characterized the species differences in hydrolases among humans and mice, rats, dogs, and cynomolgus monkeys. In this study, to expand the series of such studies, we attempted to characterize marmoset hydrolases. We measured hydrolase activities for 24 compounds using marmoset liver and intestinal microsomes, as well as recombinant marmoset carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC). The contributions of CES1, CES2, and AADAC to hydrolysis in marmoset liver microsomes were estimated by correcting the activities by using the ratios of hydrolase protein levels in the liver microsomes and those in recombinant systems. For six out of eight human CES1 substrates, the activities in marmoset liver microsomes were lower than those in human liver microsomes. For two human CES2 substrates and three out of seven human AADAC substrates, the activities in marmoset liver microsomes were higher than those in human liver microsomes. Notably, among the three rifamycins, only rifabutin was hydrolyzed by marmoset tissue microsomes and recombinant AADAC. The activities for all substrates in marmoset intestinal microsomes tended to be lower than those in liver microsomes, which suggests that the first-pass effects of the CES and AADAC substrates are due to hepatic hydrolysis. In most cases, the sums of the values of the contributions of CES1, CES2, and AADAC were below 100%, which indicated the involvement of other hydrolases in marmosets. In conclusion, we clarified the substrate preferences of hydrolases in marmosets. SIGNIFICANCE STATEMENT: This study confirmed that there are large differences in hydrolase activities between humans and marmosets by characterizing marmoset hydrolase activities for compounds that are substrates of human CES1, CES2, or arylacetamide deacetylase. The data obtained in this study may be useful for considering whether marmosets are appropriate for examining the pharmacokinetics and efficacies of new chemical entities in preclinical studies.
对于药物研发而言，药物代谢反应中的物种差异给预测人体药代动力学带来了障碍。我们对人类与小鼠、大鼠、犬类及食蟹猴之间水解酶的物种差异进行了表征。在本研究中，为扩展此类研究系列，我们试图对狨猴水解酶进行表征。我们使用狨猴肝脏和肠道微粒体以及重组狨猴羧酸酯酶（CES）1、CES2和芳基乙酰胺脱乙酰酶（AADAC）测量了24种化合物的水解酶活性。通过使用肝脏微粒体和重组系统中水解酶蛋白水平的比率校正活性，估算了CES1、CES2和AADAC对狨猴肝脏微粒体水解的贡献。对于8种人类CES1底物中的6种，狨猴肝脏微粒体中的活性低于人类肝脏微粒体中的活性。对于2种人类CES2底物和7种人类AADAC底物中的3种，狨猴肝脏微粒体中的活性高于人类肝脏微粒体中的活性。值得注意的是，在三种利福霉素中，只有利福布汀可被狨猴组织微粒体和重组AADAC水解。狨猴肠道微粒体中所有底物的活性往往低于肝脏微粒体中的活性，这表明CES和AADAC底物的首过效应是由于肝脏水解所致。在大多数情况下，CES1、CES2和AADAC贡献值的总和低于100%，这表明狨猴中还存在其他水解酶。总之，我们阐明了狨猴水解酶的底物偏好。意义声明：本研究通过表征狨猴对人类CES1、CES2或芳基乙酰胺脱乙酰酶底物的水解酶活性，证实了人类和狨猴之间水解酶活性存在很大差异。本研究获得的数据可能有助于考虑狨猴是否适合在临床前研究中用于研究新化学实体的药代动力学和疗效。
