Variability in response to clopidogrel: how important are pharmacogenetics and drug interactions?

Abstract

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel.

Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine

“…Clopidogrel is a prodrug that needs oxidative activation in vivo by CYP1A2, CYP2B6 and CYP2C19 for its anti-platelet activity [171]. Genetic polymorphisms in CYP2C19 , CYP1A2 , 2B6*6 , and CYP3A5*3 were found to be associated with the varied degree of drug–drug interactions for clopidogrel, due to its highly-complex pharmacokinetics and variable drug response as compare to other anti-platelet drugs [172], [173], [174], [175], [176].…”

Epidemiology and characteristics of adverse drug reactions caused by drug–drug interactions

“…The reduced activity of clopidogrel due to the inhibition of CYP2C19 by PPIs can be more clinically significant in patients with low activation of clopidogrel due to genetic polymorphism [90]. Codeine is bioactivated by CYP2D6 into morphine and it is inactivated by CYP3A4.…”

Addressing phenoconversion: the Achilles' heel of personalized medicine

“…Ma et al [81] have summarized and highlighted the conflicting evidence from larger, more recent studies that investigated the association between clinical outcomes following clopidogrel therapy and CYP2C19 genotype or use of proton-pump inhibitors (PPIs). A meta-analysis of data accumulated from 15 large association studies also did not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on clinical outcome [82].…”

“…A meta-analysis of data accumulated from 15 large association studies also did not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on clinical outcome [82]. Similar controversy surrounds the concurrent use of clopidogrel with omeprazole [81]. Some studies have reported adverse clinical outcomes following concurrent use of a PPI and clopidogrel compared with clopidogrel alone [83][84][85].…”