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.


CONCLUSIONS
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.
Morin
Sandrine
S
Pharmacology Department, Saint-Antoine University Hospital, Paris, France.
Bodin
Laurent
L
Loriot
Marie-Anne
MA
Thijssen
Henk H W
HH
Robert
Annie
A
Strabach
Soraya
S
Verstuyft
Céline
C
Tregouet
David-Alexandre
DA
Dubert
Liliane
L
Laurent-Puig
Pierre
P
Funck-Brentano
Christian
C
Jaillon
Patrice
P
Beaune
Philippe H
PH
Becquemont
Laurent
L
D000074:Acenocoumarol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D017931:DNA Primers; D005167:Factor VII / Q000187:drug effects; D005260:Female; D005602:France; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D000925:Anticoagulants; D017931:DNA Primers; D005167:Factor VII; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000074:Acenocoumarol