Key result
In the presence of alcohol, clopidogrel is transesterified to ethyl clopidogrel, which is further metabolized by CYP450 enzymes into ethylated forms of 2-oxo-clopidogrel and the active H4 thiol metabolite.
In vitro evidence demonstrates that alcohol alters clopidogrel metabolism, producing ethylated forms of its active metabolites, which may have pharmacological implications.
Hypothesis-generating for alcohol-clopidogrel interactions; prospective human studies needed before clinical consideration.
RATIONALE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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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Hu et al. (2014) studied this question. Clopidogrel and alcohol was evaluated on Identification of ethyl clopidogrel metabolites. In the presence of alcohol, clopidogrel is transesterified to ethyl clopidogrel, which is further metabolized by CYP450 enzymes into ethylated forms of 2-oxo-clopidogrel and the active H4 thiol metabolite.
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