The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway

• Published in: Journal of clinical pharmacology 2016-12, Vol.56 (12), p.1474-1483
• Main Author: Ford, Neville F.
• Format: Article
• Language: English
• Subjects: Animals; Citrus paradisi - metabolism; clopidogrel; CYP2C19; CYP3A4; Cytochrome P-450 CYP2C19 - metabolism; Cytochrome P-450 CYP2C19 Inhibitors - metabolism; Cytochrome P-450 CYP2C19 Inhibitors - pharmacology; drug-drug interactions; grapefruit juice; hepatosomes; Humans; Metabolism; Metabolites; omeprazole; Platelet Aggregation Inhibitors - metabolism; Platelet Aggregation Inhibitors - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; supersomes; Ticlopidine - analogs & derivatives; Ticlopidine - metabolism; Ticlopidine - pharmacology
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.769

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.