Lu Danyi, Xie Qian, Wu Baojian
Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China; Shenzhen Key Laboratory for Molecular Biology of Neural Development, Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China.
Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China.
J Pharm Biomed Anal. 2017 Oct 25;145:692-703. doi: 10.1016/j.jpba.2017.07.037. Epub 2017 Aug 4.
N-glucuronidation is an important pathway for metabolism and disposition of tertiary amines in humans. This reaction is mainly catalyzed by the enzymes UGT1A4 and UGT2B10. However, the metabolic patterns of UGT1A4- and UGT2B10-mediated N-glucuronidation are not fully clear. In this study, we first optimized in vitro reaction conditions for N-glucuronidation by using specific substrates (i.e., trifluoperazine for UGT1A4, cotinine and amitriptyline for UGT2B10). Furthermore, we found that hepatic N-glucuronidation showed significant species differences. In addition, UGT1A4 and UGT2B10 were primarily responsible for N-glucuronidation of many tertiary amines, including asenapine, loxapine, clozapine, chlorpromazine, dothiepin, doxepin, mirtazapine, mianserin, chlorcyclizine, cyclizine, promethazine, cyclobenzaprine, imatinib, retrorsine, strychnine and brucine. In conclusion, this study provides an in vitro assay system for evaluating N-glucuronidation of amines. Also, UGT1A4- and UGT2B10-mediated N-glucuronidation might play significant roles in metabolism and detoxification of tertiary amines in humans.
N-葡糖醛酸化是人体内叔胺代谢和处置的重要途径。该反应主要由UGT1A4和UGT2B10酶催化。然而，UGT1A4和UGT2B10介导的N-葡糖醛酸化的代谢模式尚不完全清楚。在本研究中，我们首先通过使用特定底物（即用于UGT1A4的三氟拉嗪、用于UGT2B10的可替宁和阿米替林）优化了N-葡糖醛酸化的体外反应条件。此外，我们发现肝脏N-葡糖醛酸化存在显著的种属差异。此外，UGT1A4和UGT2B10主要负责许多叔胺的N-葡糖醛酸化，包括阿塞那平、洛沙平、氯氮平、氯丙嗪、多塞平、多塞平、米氮平、米安色林、氯环利嗪、赛克利嗪、异丙嗪、环苯扎林、伊马替尼、倒千里光碱、士的宁和马钱子碱。总之，本研究提供了一种评估胺类N-葡糖醛酸化的体外测定系统。此外，UGT1A4和UGT2B10介导的N-葡糖醛酸化可能在人体内叔胺的代谢和解毒中发挥重要作用。
