Marta Karaźniewicz-Łada1, Dagmara Krzyżańska2, Dorota Danielak2, Janusz Rzeźniczak3, Franciszek Główka2, Marek Słomczyński3, Paweł Burchardt3,4. 1. Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781, Poznań, Poland. mkaraz@ump.edu.pl. 2. Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781, Poznań, Poland. 3. Department of Cardiology, J. Struś Hospital, ul. Szwajcarska 3, 61-285, Poznań, Poland. 4. Biology of Lipid Disorders Department, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-806, Poznań, Poland.
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.
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 CLPcarboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1C3435T 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 ABCB1C3435T 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.
Entities:
Keywords:
Atorvastatin; CYP2C19; Clopidogrel; H4 active metabolite; Rosuvastatin
Authors: Heleen J Bouman; Ankie M Harmsze; Jochem W van Werkum; Nicoline J Breet; Th O Bergmeijer; Hugo Ten Cate; Christian M Hackeng; Vera H M Deneer; Jurriën M Ten Berg Journal: Heart Date: 2011-05-31 Impact factor: 5.994
Authors: Stuart A Scott; Katrin Sangkuhl; Alan R Shuldiner; Jean-Sébastien Hulot; Caroline F Thorn; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2012-02 Impact factor: 2.089
Authors: Victor L Serebruany; Mark G Midei; Alex I Malinin; Benjamin R Oshrine; David R Lowry; David C Sane; Jean-François Tanguay; Steven R Steinhubl; Peter B Berger; Christopher M O'Connor; Charles H Hennekens Journal: Arch Intern Med Date: 2004-10-11
Authors: Richard D Finkelman; Tzung-Dau Wang; Yi Wang; Connie T Azumaya; Bruce K Birmingham; Jenny Wissmar; Rogelio Mosqueda-Garcia Journal: Clin Pharmacol Drug Dev Date: 2014-08-28