Impact of CYP3A4*1G Allele on Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel.

Background and Objectives: Resistance to the antiplatelet treatment with clopidogrel has both genetic and non-genetic causes. Polymorphic variants of cytochrome P450 3A4 isoenzyme involved in the bioactivation of clopidogrel might have an influence on responsiveness to the drug. The aim of this study was to evaluate the influence of CYP3A4*1G (IVS10+12G>A, rs2242480) on the pharmacokinetics and pharmacodynamics of clopidogrel.
Methods: CYP3A4*1G polymorphism was determined in a group of 82 patients undergoing percutaneous coronary intervention and taking 75 mg of clopidogrel daily. Concentrations of clopidogrel and its metabolites, inactive carboxylic acid derivative and two diastereoisomers of active thiol metabolite: H3 and H4, were determined by a validated HPLC-MS/MS method. Pharmacodynamic effect was measured by an impedance method with a Multiplate analyzer. Moreover, an effect of factors, such as CYP2C19 phenotype, age, gender, body mass index and interactions with drugs metabolized by CYP3A4 were also investigated.
Results: In the studied group allele frequencies were: wt-0.921, *1G-0.079. Pharmacokinetic parameters of clopidogrel and its metabolites were not significantly different in carriers of *1G allele, comparing to wt/wt homozygotes. Platelet aggregation was higher in heterozygotes than in wt/wt carriers; however, the difference was not statistically significant (p = 0.484). In a multivariate analysis, which included age, body mass index, co-morbidities and coadministered drugs, CYP3A4*1G was not a predictor of values of H3 and H4 pharmacokinetic parameters and platelet aggregation.
Conclusion: CYP3A4*1G might not be a significant contributor to the variability in pharmacokinetic and pharmacodynamic response to clopidogrel therapy.
Competing Interests: Compliance with Ethical Standards The study was supported by Polish Ministry of Science and Higher Education, Grant Number NN 405 419739 and Poznan University of Medical Sciences Grant Number 502-14-03306413-09628. The study protocol was approved by the local Ethical Committee at Poznan University of Medical Sciences. All performed procedures were in accordance with the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conflict of interest Authors declare no conflict of interest. Informed consent Informed consent was obtained from all individual participants included in the study.