title: 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.
  
  
  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.
authors.affiliation: Pharmacology Department, Saint-Antoine University Hospital, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Morin
authors.forename: Laurent
authors.initials: L
authors.lastname: Bodin
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
authors.forename: Henk H W
authors.initials: HH
authors.lastname: Thijssen
authors.forename: Annie
authors.initials: A
authors.lastname: Robert
authors.forename: Soraya
authors.initials: S
authors.lastname: Strabach
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Tregouet
authors.forename: Liliane
authors.initials: L
authors.lastname: Dubert
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: Patrice
authors.initials: P
authors.lastname: Jaillon
authors.forename: Philippe H
authors.initials: PH
authors.lastname: Beaune
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
mesh_terms: 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
chemical_list: 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