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Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin

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Abstract

Purpose

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin.

Methods

The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay.

Results

There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01).

Conclusion

The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.

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Acknowledgments

Authors would like to thank M. Rakicka, P. Kobyłka, and P. Wiącek for technical support in analysis of genetic polymorphism.

Authors’ individual contributions

All authors have contributed significantly to the work and have read and approved the manuscript for publication. M. K.Ł., and P.B. were responsible for the study concept and design. J.R. and M.S. participated in data collection. M.K.Ł., D.K., and D.D. analyzed the data. M.K.Ł., D.D., F.G., and P.B. contributed to the manuscript writing and discussion.

Funding

This study was funded by the National Science Centre (NCN) in Poland, grant number 2014/15/B/NZ7/00869.

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Correspondence to Marta Karaźniewicz-Łada.

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Karaźniewicz-Łada, M., Krzyżańska, D., Danielak, D. et al. Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin. Eur J Clin Pharmacol 76, 419–430 (2020). https://doi.org/10.1007/s00228-019-02822-x

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Keywords

  • Atorvastatin
  • Clopidogrel
  • CYP2C19
  • H4 active metabolite
  • Rosuvastatin