In vitro metabolism of L-corydalmine, a potent analgesic drug, in human, cynomolgus monkey, beagle dog, rat and mouse liver microsomes
In vitro metabolism of L-corydalmine, a potent analgesic drug, in human, cynomolgus monkey, beagle dog, rat and mouse liver microsomes
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L-紫堇碱（一种强效镇痛药）在人、食蟹猴、比格犬、大鼠和小鼠肝微粒体中的体外代谢
DOI：
10.1016/j.jpba.2016.05.024
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发表时间：
2016-09-05
影响因子：
3.4
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Tang, Xiange;Di, Xinyu;Liu, Xiaodong
L-延胡索乙素(L-延胡索乙素)是一种口服镇痛剂，在临床前模型中显示出较强的镇痛活性。本研究的目的是比较L-CDL在小鼠、大鼠、猴、狗和人肝微粒体中的代谢情况。用LC-QJTOF从五种动物的肝微粒体中鉴定出六种代谢物(M1-M6)。L-CDL的代谢包括O-去甲基化(M1-3)和羟基化(M4-6)。5种植物中以脱甲基代谢产物为主，占84%以上。人肝微粒体(HLM)和人重组细胞色素P450的化学抑制实验结果表明，细胞色素P450对M1和M2的形成有很强的催化作用，而对M2的形成也有一定的催化作用。M3和羟基代谢产物(M4和M5)的形成主要由CYP3A4催化。进一步研究表明，M1和M2是HLM中的主要代谢物。还研究了HLM和重组细胞色素P450中M1和M2的形成动力学。结果表明，在HLM和重组CYP2D6中，M1和M2的形成符合双相动力学，而用Sigmoid V-max模型更好地拟合了重组CYP2C9和CYP2C19的M2形成。CYP2D6对HLM中M1和M2组的贡献分别为75.3%和50.7%。而细胞色素P450 C9和细胞色素P450 C19对M2形成的贡献分别为5.0%和4.1%。这些数据表明，M1和M2是HLM的主要代谢物，而CYP2D6是其形成的主要酶。(C)2016爱思唯尔B.V.保留所有权利。
L-Corydalmine (l-CDL) was under development as an oral analgesic agent, exhibiting potent analgesic activity in preclinical models. The objective of this study was to compare metabolic profiles of l-CDL in liver microsomes from mouse, rat, monkey, dog and human. Six metabolites (M1-M6) were identified using LC-QJTOF in liver microsomes from the five species. The metabolism of l-CDL included O-demethylation (M1-3) and hydroxylation (M4-6). The desmethyl metabolites were the major ones among the five species, which accounted for more than 84%. Data from chemical inhibition in human liver microsomes (HLM) and human recombinant CYP450s demonstrated that CYP2D6 exhibited strong catalytic activity towards M1 and M2 formations, while CYP2C9 and CYP2C19 also catalyzed M2 formation. Formations of M3 and hydroxyl metabolites (M4 and M5) were mainly catalyzed by CYP3A4. Further studies showed that Ml and M2 were main metabolites in HLM. The kinetics of M1 and M2 formations in HLM and recombinant CYP450s were also investigated. The results showed that M1 and M2 formations in HLM and recombinant CYP2D6 characterized biphasic kinetics, whereas sigmoid V-max model was better used to fit M2 formation by recombinant CYP2C9 and CYP2C19. The contributions of CYP2D6 to M1 and M2 formations in HLM were estimated to be 75.3% and 50.7%, respectively. However, the contributions of CYP2C9 and CYP2C19 to M2 formation were only 5.0% and 4.1%, respectively. All these data indicated that M1 and M2 were main metabolites in HLM, and CYP2D6 was the primary enzyme responsible for their formations. (C) 2016 Elsevier B.V. All rights reserved.