title: Impact of CYP2C9 polymorphisms on the vulnerability to pharmacokinetic drug-drug interactions during acenocoumarol treatment.
abstract: OBJECTIVE
  The objective of this study was to investigate the impact of CYP2C9 polymorphisms and drug-drug interactions on the risk of overanticoagulation in patients treated with acenocoumarol, a vitamin K antagonist.
  
  
  METHODS
  A prospective observational study was performed on patients starting acenocoumarol (n = 115). CYP2C9 genotypes were assessed. Data on International Normalized Ratio, comedications and doses of acenocoumarol were collected during the first 35 days of therapy. Overanticoagulation was defined as the occurrence of at least one International Normalized Ratio ≥4.
  
  
  RESULTS
  The presence of a CYP2C9 inhibitor or a CYP2C9 polymorphisms statistically increased the risk of overanticoagulation (hazard ratio [HR]: 2.8, p < 0.001 and HR: 1.7, p = 0.04, respectively). The presence of CYP2C9 polymorphisms almost tripled the risk of overanticoagulation (HR: 2.91, p = 0.01) in the presence of a clinically significant drug-drug interaction.
  
  
  CONCLUSIONS
  These findings support the fact that CYP2C9 genotyping could be useful to identify patients requiring closer monitoring, especially when a drug-drug interaction is expected.
authors: Division of Clinical Pharmacology & Toxicology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland.
authors: Liliane
authors: L
authors: Gschwind
authors: Victoria
authors: V
authors: Rollason
authors: Françoise
authors: F
authors: Boehlen
authors: Michela
authors: M
authors: Rebsamen
authors: Christophe
authors: C
authors: Combescure
authors: Michèle
authors: M
authors: Grünenwald
authors: Alain
authors: A
authors: Matthey
authors: Pascal
authors: P
authors: Bonnabry
authors: Pierre
authors: P
authors: Dayer
authors: Jules Alexandre
authors: JA
authors: Desmeules
mesh_terms: D000074:Acenocoumarol / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001778:Blood Coagulation Disorders / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000074:Acenocoumarol