Implications of Inter-Individual Differences in Clopidogrel Metabolism, with Focus on Pharmacogenetics

Abstract

Increasing evidence for the role of pharmacogenetics in treatment resistance to the antiplatelet agent clopidogrel has been gained during the last years. Apart from CYP2C19 genetic polymorphisms, nongenetic factors, particularly drug-drug interactions, age and other clinical characteristics influence the interindividual variability in clopidogrel response to varying degrees. The present article reviews the so far accumulated evidence on the role of pharmacogenetic traits influencing CYP-activity as determinants of the antiplatelet response to clopidogrel, and its clinical implications. The genetic variation in CYP2C19 activity seems to influence short- and long-term antithrombotic effects of clopidogrel to a substantial extent. Prediction models for clopidogrel non-responsiveness that include CYP2C19 genotyping together with relevant non-genetic risk factors are needed to be verified for their potential benefit in individualization of antithrombotic therapy.

Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis

“…Structure of clopidogrel, metabolites, and metabolic pathwaysThere is large inter-individual variability in clopidogrel response. Depending on the criteria used, approximately 15-40% are considered non-responders with high residual platelet aggregation[109], i.e. "clopidogrel-resistant".…”

Antiplatelet agents: Is twice a day a better strategy?

“…These observations strongly suggest the notion that identification and quantification of platelet-monocyte binding in patients with chest pain may provide key early in vivo evidence of vascular injury responses and offer opportunities for novel therapeutic intervention strategies in the treatment of ACS [15].…”

“…On the other hand, recent genetic studies have also associated several polymorphism to a reduced response to ASA and clopidogrel [15]. Of interest, non-responders individuals have been associated with 5-fold greater risk of suffering CV events than those considered responders [39].…”

“…However, some patients develop recurrent CV events besides the antiplatelet treatment [11][12][13]. Different hypothesis tried to explain this results, including genetic differences [14][15][16][17] but more recently the relationship between platelet turn-over and an hyper-inflammatory status are emerging [18][19][20][21].…”

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“…Currently the majority of data assessing clopidogrel therapy focuses on the most common allelic variants of CYP2C19 (*2 and *3), which accounts for 95% of poor metabolizer (PM) phenotypes (Simon et al, 2009). Other more rare alleles causing deficient metabolism are CYP2C19*4, *5, *6, *7, *8, and CYP2C19*17 which on the other hand, results in increased enzyme activity (Dahl and Gunes, 2010).…”