The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway.

Article Details

Citation

Ford NF

The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway.

J Clin Pharmacol. 2016 Dec;56(12):1474-1483. doi: 10.1002/jcph.769. Epub 2016 Jun 22.

PubMed ID
27196064 [View in PubMed
]
Abstract

The major metabolic pathway of clopidogrel is conversion to carboxylic acid by an esterase (CES1), forming clopidogrelic acid (SR26334) that is inactive. There is agreement on the structure of the active metabolite; however, there are differing views about the mechanism of its formation. Sanofi studied the conversion of clopidogrel to the active metabolite using human liver microsomes. It was concluded that 2-oxo-clopidogrel was formed via CYP3A oxidation. From a subsequent in vitro study by Sankyo of the metabolism of clopidogrel using recombinant DNA CYPs, it was concluded that CYP2C19 was the major oxidative pathway. Such CYPs can give false-negative results particularly with drugs such as clopidogrel that have high first-pass metabolism in the enterocyte. CYP3A is present in the enterocyte but not CYP2C19. However, the view that clopidogrel is a CYP2C19 substrate was reinforced by a finding that omeprazole, a CYP2C19 inhibitor, reduced the ability of clopidogrel to inhibit platelet aggregation. The drug-drug interaction study of clopidogrel with omeprazole had the effect of reducing the area under the curve (AUC) of the clopidogrel active metabolite by 45%. However, a drug interaction study with a CYP3A inhibitor, grapefruit juice, caused a 6-fold reduction in the AUC of the active metabolite. Clopidogrel is therefore now considered to be primarily a CYP3A4/5 substrate. CYP2C19 has a minor role whose effect can be detected using a sensitive methodology such as platelet aggregometry.

DrugBank Data that Cites this Article

Drug Enzymes
Drug Enzyme Kind Organism Ph值armacological Action Actions
Clopidogrel Cytochrome P450 2C19 Protein Humans
No
Substrate
Details
Drug InteractionsLearn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
Drugs Interaction
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more