CYP2C19 genotype, but not PON1, was predictive of clopidogrel active metabolite levels and antiplatelet response in healthy subjects.
Observational (n=21)
Does CYP2C19 or PON1 genotype predict clopidogrel active metabolite formation and antiplatelet response in healthy subjects?
CYP2C19, rather than PON1, is the primary driver of clopidogrel bioactivation and antiplatelet response, confirming its utility as a pharmacokinetic predictor.
AIMS: It is thought that clopidogrel bioactivation and antiplatelet response are related to cytochrome P450 2C19 (CYP2C19). However, a recent study challenged this notion by proposing CYP2C19 as wholly irrelevant, while identifying paraoxonase-1 (PON1) and its Q192R polymorphism as the major driver of clopidogrel bioactivation and efficacy. The aim of this study was to systematically elucidate the mechanism and relative contribution of PON1 in comparison to CYP2C19 to clopidogrel bioactivation and antiplatelet response. METHODS AND RESULTS: First, the influence of CYP2C19 and PON1 polymorphisms and plasma paraoxonase activity on clopidogrel active metabolite (H4) levels and antiplatelet response was assessed in a cohort of healthy subjects (n = 21) after administration of a single 75 mg dose of clopidogrel. There was a remarkably good correlation between H4 AUC (0-8 h) and antiplatelet response (r2 = 0.78). Furthermore, CYP2C19 but not PON1 genotype was predictive of H4 levels and antiplatelet response. There was no correlation between plasma paraoxonase activity and H4 levels. Secondly, metabolic profiling of clopidogrel in vitro confirmed the role of CYP2C19 in bioactivating clopidogrel to H4. However, heterologous expression of PON1 in cell-based systems revealed that PON1 cannot generate H4, but mediates the formation of another thiol metabolite, termed Endo. Importantly, Endo plasma levels in humans are nearly 20-fold lower than H4 and was not associated with any antiplatelet response. CONCLUSION: Our results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response.
“It's indisputable that this particular genotype influences the effectiveness of clopidogrel, a very commonly prescribed heart medication. There are data from clinical trials and observational studies to support genotyping and its ability to improve patient outcomes and decrease bleeding risk if you use it to guide therapy. Many of the barriers that once limited CYP2C19 genotyping in clinical practice have now been removed.”
Gong et al. (Mon,) conducted a observational in Healthy subjects (n=21). CYP2C19 and PON1 polymorphisms was evaluated on Clopidogrel active metabolite (H4) levels and antiplatelet response. CYP2C19 genotype, but not PON1, was predictive of clopidogrel active metabolite levels and antiplatelet response in healthy subjects.