Identification of alcohol-dependent clopidogrel metabolites using conventional liquid chromatography/triple quadrupole mass spectrometry.
Identification of alcohol-dependent clopidogrel metabolites using conventional liquid chromatography/triple quadrupole mass spectrometry.
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DOI：
10.1002/rcm.6901
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发表时间：
2014-06-15
影响因子：
2
通讯作者：
Parker, Robert B.
中科院分区：
文献类型：
--
作者：
Hu, Zhe-Yi;Laizure, S. Casey;Herring, Vanessa L.;Parker, Robert B.
氯吡格雷 (CLO) 是一种前药，用于预防接受经皮冠状动脉介入治疗或心肌梗塞患者的缺血事件。先前的一项研究发现，乙基氯吡格雷 (ECLO) 是在人肝微粒体中与酒精一起孵育时，通过 CLO 的酯交换反应形成的。我们假设 ECLO 将进一步代谢，并开发了一种检测方法来鉴定其代谢物。开发了液相色谱/三重四极杆质谱 (LC-MS/MS) 方法来鉴定 ECLO 的代谢物。根据预测的ECLO代谢途径，利用前体-产物离子对筛选人肝脏S9级分中ECLO可能的代谢物。随后，通过产物离子扫描的结果对检测到的代谢物进行表征。在酒精存在下，CLO 酯交换为 ECLO，ECLO 进一步氧化形成乙基化 2-氧代氯吡格雷和几种乙基化硫醇代谢物，包括 H4 活性代谢物的乙基化形式。与酒精进行酯交换形成的 ECLO 会被 CYP450 酶代谢，产生乙基化形式的 2-氧代-氯吡格雷和活性 H4 硫醇代谢物。
Clopidogrel (CLO) is a prodrug used to prevent ischemic events in patients undergoing percutaneous coronary intervention or with myocardial infarction. A previous study found ethyl clopidogrel (ECLO) is formed by transesterification of CLO when incubated with alcohol in human liver microsomes. We hypothesize that ECLO will be subject to further metabolism and developed an assay to identify its metabolites. A liquid chromatography/triple quadrupole mass spectrometry (LC-MS/MS) method was developed to identify metabolites of ECLO. According to the predicted metabolic pathway of ECLO, precursor–product ion pairs were used to screen the possible metabolites of ECLO in human liver S9 fractions. Subsequently, the detected metabolites were characterized by the results of product ion scan. In the presence of alcohol, CLO was tranesterified to ECLO, which was further oxidized to form ethylated 2-oxo-clopidogrel and several ethylated thiol metabolites including the ethylated form of the H4 active metabolite. The ECLO formed by transesterification with alcohol is subject to metabolism by CYP450 enzymes producing ethylated forms of 2-oxo-clopidogrel and the active H4 thiol metabolite.
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在体外dabigatran et催化代谢的研究中，常规的液相色谱/三极质质谱法代谢物鉴定和半定量估计方法。
影响因子：
4.3
作者：
Hu, Zhe-Yi;Parker, Robert B.;Herring, Vanessa L.;Laizure, S. Casey
通讯作者：
Laizure, S. Casey
影响因子：
3
作者：
Kabashima, Tsutomu;Yu, Zhiqiang;Kai, Masaaki
通讯作者：
Kai, Masaaki
DOI：
10.1016/j.jchromb.2012.11.005
发表时间：
2012-12-12
影响因子：
3
作者：
Karazniewicz-Lada, Marta;Danielak, Dorota;Glowka, Franciszek
通讯作者：
Glowka, Franciszek
影响因子：
6.7
作者：
Simon, T.;Bhatt, D. L.;Dubar, M.
通讯作者：
Dubar, M.
影响因子：
6.7
作者：
Tuffal, Gilles;Roy, Sebastien;Sultan, Eric
通讯作者：
Sultan, Eric