Tang Xiange, Di Xinyu, Zhong Zeyu, Xie Qiushi, Chen Yang, Wang Fan, Ling Zhaoli, Xu Ping, Zhao Kaijing, Wang Zhongjian, Liu Li, Liu Xiaodong
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
J Pharm Biomed Anal. 2016 Sep 5;128:98-105. doi: 10.1016/j.jpba.2016.05.024. Epub 2016 May 17.
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-Q/TOF 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 M1 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 Vmax 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.
左旋紫堇明碱（l-CDL）曾作为一种口服镇痛药进行研发，在临床前模型中显示出强效镇痛活性。本研究的目的是比较l-CDL在小鼠、大鼠、猴、狗和人类肝脏微粒体中的代谢谱。使用液相色谱-四极杆/飞行时间质谱（LC-Q/TOF）在这五个物种的肝脏微粒体中鉴定出了六种代谢物（M1-M6）。l-CDL的代谢包括O-去甲基化（M1-3）和羟基化（M4-6）。去甲基代谢物是这五个物种中的主要代谢物，占比超过84%。来自人肝脏微粒体（HLM）和人重组细胞色素P450（CYP450）的化学抑制数据表明，CYP2D6对M1和M2的形成表现出很强的催化活性，而CYP2C9和CYP2C19也催化M2的形成。M3和羟基代谢物（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CYP450中M1和M2形成的动力学。结果表明，HLM和重组CYP2D6中M1和M2的形成具有双相动力学特征，而S形Vmax模型更适合用于拟合重组CYP2C9和CYP2C19催化的M2形成。CYP2D6对HLM中M1和M2形成的贡献估计分别为75.3%和50.7%。然而，CYP2C9和CYP2C19对M2形成的贡献分别仅为5.0%和4.1%。所有这些数据表明，M1和M2是HLM中的主要代谢物，CYP2D6是其形成的主要负责酶。
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