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Strain and sex differences in drug hydrolase activities in rodent livers.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-11-11 , DOI: 10.1016/j.ejps.2019.105143 Fumiya Kisui 1 , Tatsuki Fukami 2 , Masataka Nakano 2 , Miki Nakajima 2
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-11-11 , DOI: 10.1016/j.ejps.2019.105143 Fumiya Kisui 1 , Tatsuki Fukami 2 , Masataka Nakano 2 , Miki Nakajima 2
Affiliation
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Carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC) are the major drug hydrolases in humans, and they have different substrate preferences. Because rodents are widely used in preclinical studies, we aimed to clarify the extent of the species, strain, and sex differences in hydrolase activity in rats and mice. Hydrolase activities for 24 compounds were evaluated in Fischer 344, Sprague-Dawley, and Wistar-Imamichi rat liver microsomes (RLM) and Balb/c, C3H/He, C57BL/6J, and ddY mouse liver microsomes (MLM) by comparing the results with the activities in human liver microsomes (HLM). Imidapril hydrolase activities in RLM from all strains were substantially higher than those in MLM and HLM, whereas oseltamivir was hardly hydrolyzed in rodents, although both are specific substrates of CES1 in humans. In rats, males tended to show higher hydrolase activities for most human CES1 substrates than females. Hydrolase activities for irinotecan and procaine, which are CES2 substrates in humans, tended to be higher in RLM and MLM than in HLM. Rifamycins, substrates of human AADAC, were not hydrolyzed in RLM and MLM. The results of this study provide important information about the species, strain, and sex differences in hydrolase activities in rats and mice.
中文翻译：
啮齿动物肝脏中药物水解酶活性的应变和性别差异。
羧基酯酶（CES）1，CES2和芳基乙酰胺脱乙酰基酶（AADAC）是人类主要的药物水解酶，它们具有不同的底物偏好。由于啮齿动物在临床前研究中被广泛使用，因此我们旨在阐明大鼠和小鼠中水解酶活性的种类，品系和性别差异的程度。通过比较结果，在Fischer 344，Sprague-Dawley和Wistar-Imamichi大鼠肝微粒体（RLM）和Balb / c，C3H / He，C57BL / 6J和ddY小鼠肝微粒体（MLM）中评估了24种化合物的水解酶活性与人类肝微粒体（HLM）中的活性有关。尽管所有菌株均为人类CES1的特异底物，但所有菌株RLM中的咪达普利水解酶活性均明显高于MLM和HLM中的奥司他韦，而奥司他韦在啮齿动物中几乎不被水解。在大鼠中 对于大多数人类CES1底物，雄性倾向于表现出比雌性更高的水解酶活性。伊立替康和普鲁卡因的水解酶活性是人类的CES2底物，在RLM和MLM中的水解酶活性往往高于HLM。利福霉素是人ADAC的底物，在RLM和MLM中未水解。这项研究的结果提供了有关大鼠和小鼠水解酶活性的种类，品系和性别差异的重要信息。
更新日期：2019-11-11
中文翻译：
啮齿动物肝脏中药物水解酶活性的应变和性别差异。
羧基酯酶（CES）1，CES2和芳基乙酰胺脱乙酰基酶（AADAC）是人类主要的药物水解酶，它们具有不同的底物偏好。由于啮齿动物在临床前研究中被广泛使用，因此我们旨在阐明大鼠和小鼠中水解酶活性的种类，品系和性别差异的程度。通过比较结果，在Fischer 344，Sprague-Dawley和Wistar-Imamichi大鼠肝微粒体（RLM）和Balb / c，C3H / He，C57BL / 6J和ddY小鼠肝微粒体（MLM）中评估了24种化合物的水解酶活性与人类肝微粒体（HLM）中的活性有关。尽管所有菌株均为人类CES1的特异底物，但所有菌株RLM中的咪达普利水解酶活性均明显高于MLM和HLM中的奥司他韦，而奥司他韦在啮齿动物中几乎不被水解。在大鼠中 对于大多数人类CES1底物，雄性倾向于表现出比雌性更高的水解酶活性。伊立替康和普鲁卡因的水解酶活性是人类的CES2底物，在RLM和MLM中的水解酶活性往往高于HLM。利福霉素是人ADAC的底物，在RLM和MLM中未水解。这项研究的结果提供了有关大鼠和小鼠水解酶活性的种类，品系和性别差异的重要信息。
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