Pharmacogenetics of acenocoumarol pharmacodynamics.

ABSTRACT

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.