title: Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis.
abstract: BACKGROUND
  The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT).
  
  
  METHODS
  476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined.
  
  
  RESULTS
  Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p=0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p<0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p=0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p=0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol.
  
  
  CONCLUSIONS
  This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol.
authors: Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore-560029, India.
authors: Tanima
authors: T
authors: De
authors: Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore-560029, India. Electronic address: rita@nimhans.kar.nic.in.
authors: Rita
authors: R
authors: Christopher
authors: Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore-560029, India.
authors: Dindagur
authors: D
authors: Nagaraja
mesh_terms: D000074:Acenocoumarol / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D020767:Intracranial Thrombosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D015995:Prevalence; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D055815:Young Adult
chemical_list: D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000074:Acenocoumarol
keywords: Acenocoumarol; Cerebral venous thrombosis; Cytochrome P450 2C9; Phenytoin; Polymorphism