Identification of Cytochrome P450 (CYP) Isoforms involved in the Metabolism of Corynoline, and Assessment of its Herb-Drug Interactions

被引:65
作者
Fang, Zhong-Ze [1 ,2 ]
Zhang, Yan-Yan [1 ,2 ]
Ge, Guang-Bo [1 ,2 ]
Liang, Si-Cheng [1 ,2 ]
Sun, Dong-Xue
Zhu, Liang-Liang [1 ,2 ]
Dong, Pei-Pei [1 ,2 ]
Cao, Yun-Feng [3 ]
Yang, Ling [1 ]
机构
[1] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China
[2] Chinese Acad Sci, Grad Sch, Beijing 100049, Peoples R China
[3] Shenyang Pharmaceut Univ, Sch Tradit Chinese Med, Shenyang, Peoples R China
基金
中国国家自然科学基金;
关键词
corynoline; cytochrome P450 (CYP); drug-herb interaction; time-dependent inhibition (TDI); CORYDALIS-INCISA; AERIAL PARTS; INHIBITION; ALKALOIDS; P450S;
D O I
10.1002/ptr.3255
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Corynoline, an isoquinoline alkaloid isolated from the genus Corydalis, has been demonstrated to show multiple pharmacological effects including inhibition of acetylcholinesterase, inhibition of cell adhesion, fungitoxic and cytotoxic activity. The present study focused on its metabolism and metabolism-based herb drug interactions. After corynoline was incubated with human liver microsomes (HLMs) in the presence of NADPH, two metabolites (M-1 and M-2) were formed. Chemical inhibition experiments and assays with recombinant CYP isoforms showed that CYP2C9 was mainly involved in the formation of M-1 and CYP3A4 mainly catalysed the production of M-2. Among seven major CYP isoforms tested, corynoline showed strong inhibitory effects on the activities of CYP3A4 and CYP2C9, with an IC50 of 3.3 +/- 0.9 mu M and 31.5 +/- 0.5 mu M, respectively. Kinetic analysis showed that inhibition of CYP3A4 by corynoline was best fit to a noncompetitive manner with K-i of 3.2 mu M, while inhibition of CYP2C9 by corynoline was best fit to a competitive manner with K-i of 6.3 mu M. Additionally, corynoline exhibited time-dependent inhibition (TDI) toward CYP3A4. The inactivation kinetic parameters (K-I and k(inact)) were calculated to be 6.8 mu M and 0.07 min(-1), respectively. These data are of significance for the application of corynoline and corynoline-containing herbs. Copyright (C) 2010 John Wiley & Sons, Ltd.
引用
收藏
页码:256 / 263
页数:8
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