Pharmacogenetics of acenocoumarol pharmacodynamics.
OBJECTIVE: The aim of this study was to investigate the respective contribution of the different cytochrome P450 ( CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response. METHODS: A total of 263 healthy volunteers were genotyped for CYP2C9*2, CYP2C9*3, CYP2C9*4, and CYP2C9*5 alleles, as well as for the nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase 1 genetic polymorphism (NQO1*2). Moreover, the 5'-flanking region of the CYP2C9 gene was investigated for new polymorphisms, and haplotype analysis was then performed. Finally, CYP2C9 phenotype was evaluated after a single oral dose of 4 mg of acenocoumarol. Factor VII coagulant activity was measured before and 24 hours after acenocoumarol intake. RESULTS: The CYP2C9*3 allele was the only nonsynonymous single nucleotide polymorphism (SNP) influencing acenocoumarol pharmacodynamics; the percentages of remaining factor VII were 60% +/- 19%, 39% +/- 17%, and 17% for CYP2C9*1/CYP2C9*1, CYP2C9*1/CYP2C9*3, and CYP2C9*3/CYP2C9*3 subjects, respectively (P =.001). Among the white subjects, the CYP2C9 promoter showed the existence of 6 SNPs at positions G-1538A, T-1189C, G-1097A, G-982A, T-640 del, and G-620T with allelic frequencies of 0.085, 0.0398, 0.136, 0.086, 0.005, and 0.0138, respectively. Four major haplotypes could be inferred among white subjects. The haplotype that contains the CYP2C9*3 allele was the only one influencing acenocoumarol pharmacodynamics, explaining 14.3% of its interindividual variability. Body weight explained 5% of acenocoumarol pharmacodynamic variability, whereas the NQO1*2 allele had no significant effect. CONCLUSION: Overall, CYP2C9-related genetic variability accounts for 14% of the interindividual variability in acenocoumarol pharmacodynamic response. The information found by haplotype analysis is mainly related to the CYP2C9*3 SNP.[1]References
- Pharmacogenetics of acenocoumarol pharmacodynamics. Morin, S., Bodin, L., Loriot, M.A., Thijssen, H.H., Robert, A., Strabach, S., Verstuyft, C., Tregouet, D.A., Dubert, L., Laurent-Puig, P., Funck-Brentano, C., Jaillon, P., Beaune, P.H., Becquemont, L. Clin. Pharmacol. Ther. (2004) [Pubmed]
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