title: Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions.
abstract: BACKGROUND
  Cytocbrome P450 (CYP) 2C9 polymorphism affects the warfarin dosage requirement in stable outpatients. However, it is not known whether the CYP2C9 genotype contributes to the variability in warfarin dosage in the presence of drug-disease and drug-drug interactions.
  
  
  OBJECTIVE
  The aim of this study was to examine the effects of CYP2C9 genetic polymorphism on warfarin dosage requirements in patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin.
  
  
  METHODS
  This prospective, observational study was conducted at Hadassah University Hospital, Jerusalem, Israel. Data from consecutive patients treated with warfarin for at least 3 months and admitted to the internal medicine ward were eligible for inclusion. Clinical data, international normalized ratio (INR), and warfarin dosage were recorded from medical records. The CYP2C9 genotype was determined using polymerase chain reaction restriction fragment length polymorphism, and plasma concentrations of (S)- and (R)-warfarin were determined by high-performance liquid chromatography using chiral methods.
  
  
  RESULTS
  One hundred nineteen subjects (52% women) were studied. Mean age was 65.8 years (95% CI, 63.1-68.4), and weight was 74.9 kg (95% CI, 72.1-77.7). The mean warfarin dosage was 33% lower in patients with the CYP2C9-*1/*3 genotype (mean [SEM], 0.045 [0.006] mg/kg x d(-1)) compared with the CYP2C9-*1/*1 genotype (0.067 [0.004] mg/kg x d(-1)) (P=0.008); an intermediate value was found for the CYP2C9-*1/*2 genotype (0.062 [0.008] mg/kg x d(-1)). However, despite the lower dosage, INR was significantly higher in patients with the *1/*3 genotype (mean [95% CI], 3.29 [2.44-4.14]) (n=18) compared with the *1/*1 genotype (2.52 [2.34-2.71]) (n=64) (P=0.029). In addition to genotype, older age, congestive heart failure (CHF), and treatment with antibiotics were associated with lower warfarin dosages, whereas treatment with drug-metabolism inducers was associated with higher warfarin dosages. In addition, the ratios of (S)- to (R)-warfarin concentrations were significantly higher in patients with *1/*3 compared with those in patients with the *1/*1 genotype.
  
  
  CONCLUSIONS
  In this study population of patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin, CYP2C9 *1/*3 genotype, older age, CHF, and the use of antibiotics were associated with lower warfarin dosage requirements. The CYP2C9*1/*3 genotype, compared with CYP2C9 *1/*1, was associated with 33% lower mean warfarin dosage requirements and higher INR values, which were higher than the upper therapeutic range of INR (ie, 3). Genetic CYP2C9 polymorphism contributed to the variability in warfarin dosage requirements in the presence of drug-disease and drug-drug interactions.
authors.affiliation: Division o f Medicine, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.forename: Simcha
authors.initials: S
authors.lastname: Blotnik
authors.forename: Amir
authors.initials: A
authors.lastname: Elami
authors.forename: Irena
authors.initials: I
authors.lastname: Krasilnikov
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Caraco
mesh_terms: D000367:Age Factors; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000925:Anticoagulants / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D015897:Comorbidity; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D019370:Observation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D014859:Warfarin / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases