Human Liver Cytochrome P450 Enzymes and Microsomal Thiol Methyltransferase Are Involved in the Stereoselective Formation and Methylation of the Pharmacologically Active Metabolite of Clopidogrel
文献类型：期刊论文
| 作者 | Liu, Cai; Chen, Zhaoqiang; Zhong, Kan; Li, Liang ; Zhu, Weiliang; Chen, Xiaoyan; Zhong, Dafang
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| 刊名 | DRUG METABOLISM AND DISPOSITION
 |
| 出版日期 | 2015-10 |
| 卷号 | 43期号:10页码:1632-1641 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.115.064949 |
| 文献子类 | Article |
| 英文摘要 | Clopidogrel, a thienopyridine antiplatelet prodrug, is metabolized by oxidation to 2-oxo-clopidogrel, followed by conversion to its pharmacologically active thiol metabolite. After oral administration of clopidogrel to humans, two thiol isomers (H3 and H4) are observed in plasma, with similar concentrations, and only H4 is active in humans. In this work, the mechanism of stereoselectivity in the formation and S-methylation of H3 and H4 was investigated in vitro. The two diastereomers of 2-oxo-clopidogrel were epimerized rapidly at physiologic pH. The intrinsic clearance (CLint) for H3 formation from 2-oxo-clopidogrel in human liver microsomes (HLMs) was 3.1-fold higher than that for H4 formation, indicating stereoselective metabolism. Kinetic studies using expressed enzymes demonstrated that the contributions of CYP2B6, CYP2C19, and CYP3A4 to the formation of H4 from 2-oxo-clopidogrel were 18.5%, 26.1%, and 53.5%, respectively. The CLint ratios of H3 formation to H4 formation from 2-oxo-clopidogrel by CYP2B6, CYP2C19, and CYP3A4 were 2.2, 1.0, and 1.7, respectively. In HLMs, H3 and H4 were further S-methylated, and the S-methylation was inhibited by 2,3-dichloromethyl benzylamine, indicating the involvement of thiol S-methyltransferase. The CLint value for the S-methylation of H3 in HLMs was 98.1-fold higher than that for H4. The stereoselective formation of H3 from 2-oxo-clopidogrel and the stereoselective S-methylation of H3 may lead to the similar exposure levels of H3 and H4 previously reported in humans. The epimerization of 2-oxo-clopidogrel and the variations of thiol S-methyltransferase may affect the exposure to H4 in humans. |
| WOS关键词 | ANTIPLATELET ; BIOACTIVATION ; RESISTANCE ; TICLOPIDINE ; REACTIVITY ; PRASUGREL ; VICAGREL ; THERAPY ; P450 |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000369536000013 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276374]  |
| 专题 | 上海药物代谢研究中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zhong, Dafang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Cai,Chen, Zhaoqiang,Zhong, Kan,et al. Human Liver Cytochrome P450 Enzymes and Microsomal Thiol Methyltransferase Are Involved in the Stereoselective Formation and Methylation of the Pharmacologically Active Metabolite of Clopidogrel[J]. DRUG METABOLISM AND DISPOSITION,2015,43(10):1632-1641. |
| APA | Liu, Cai.,Chen, Zhaoqiang.,Zhong, Kan.,Li, Liang.,Zhu, Weiliang.,...&Zhong, Dafang.(2015).Human Liver Cytochrome P450 Enzymes and Microsomal Thiol Methyltransferase Are Involved in the Stereoselective Formation and Methylation of the Pharmacologically Active Metabolite of Clopidogrel.DRUG METABOLISM AND DISPOSITION,43(10),1632-1641. |
| MLA | Liu, Cai,et al."Human Liver Cytochrome P450 Enzymes and Microsomal Thiol Methyltransferase Are Involved in the Stereoselective Formation and Methylation of the Pharmacologically Active Metabolite of Clopidogrel".DRUG METABOLISM AND DISPOSITION 43.10(2015):1632-1641. |
入库方式： OAI收割
来源：上海药物研究所
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