Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans
文献类型：期刊论文
| 作者 | Jiang, Jinfang1,2; Chen, Xiaoyan1,2 ; Zhong, Dafang1,2
|
| 刊名 | FRONTIERS IN PHARMACOLOGY
 |
| 出版日期 | 2017-11-20 |
| 卷号 | 8 |
| 关键词 | arylacetamide deacetylase vicagrel clopidogrel hydrolytic metabolism |
| ISSN号 | 1663-9812 |
| DOI | 10.3389/fphar.2017.00846 |
| 文献子类 | Article |
| 英文摘要 | Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxoclopidogrel production from vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxoclopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of vicagrel in humans, which can help further understand the bioactivation mechanism of vicagrel and the variations in the treatment responses to vicagrel and clopidogrel. |
| WOS关键词 | STENT THROMBOSIS ; CLOPIDOGREL ; PHARMACOKINETICS ; METABOLISM ; PRASUGREL ; CHINESE ; CARBOXYLESTERASES ; DETERMINANT ; ACTIVATION ; ENZYME |
| 资助项目 | Young Science Foundation of the National Natural Science Foundation of China[81703602] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000415673900001 |
| 出版者 | FRONTIERS MEDIA SA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272399]  |
| 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 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, State Key Lab Drug Res, Shanghai, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Jiang, Jinfang,Chen, Xiaoyan,Zhong, Dafang. Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans[J]. FRONTIERS IN PHARMACOLOGY,2017,8. |
| APA | Jiang, Jinfang,Chen, Xiaoyan,&Zhong, Dafang.(2017).Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans.FRONTIERS IN PHARMACOLOGY,8. |
| MLA | Jiang, Jinfang,et al."Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans".FRONTIERS IN PHARMACOLOGY 8(2017). |
入库方式： OAI收割
来源：上海药物研究所
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