engleski

Effect of cytochrome P450 CYP2C9 genotype on warfarin sensibility

Warfarin is the most commonly used oral anticoagulant for the prevention and treatment of patients with thromboembolic disorders. The dosage required to achieve the optimal therapeutic effect varies up to 120-fold between individuals. Interindividual variability in responses to warfarin therapy is attributed to a multitude of factors, including the genetic polymorphism of the principal enzyme involved in warfarin metabolism, the cytochrome P450 CYP2C9. Besides the wild-type allele CYP2C9*1, two relatively common variant alleles of the CYP2C9 gene with reduced activity have been identified, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu). The effect of CYP2C9 genotype on warfarin sensibility was studied in 63 warfarin-treated patients. For every patient the weekly dose of warfarin was recorded and prothrombin time was determined. Genotyping for the CYP2C9*2 and CYP2C9*3 was performed by PCR RFLP. The distribution of the CYP2C9 genotypes was as follows: 66.7% for CYP2C9*1/*1, 20.6% for CYP2C9*1/*2, 11.1% for CYP2C9*1/*3 and 1.6% for CYP2C9*2/*3. No patient were homozygous for the CYP2C9*2 or CYP2C9*3 allele. Allele frequencies for CYP2C9*1, CYP2C9*2, and CYP2C9*3 were 0.83, 0.11 and 0.06. Therapeutic INR values (INR=2.0-3.5) were achieved in 30 patients, whereas subtherapeutic INR values (INR=1.5-2.0) were obtained in 19 patients. In 10 patients the INR values were below 1.5, and were above 3.5 in 4 patients. Weekly warfarin doses required to achieve the therapeutic INR range (2.0-3.5) ranged between 9.0-105 mg/week (median: 33.4 mg), and were significantly different in patients with the wild-type CYP2C9*1/*1 (median dose: 40.5 mg/week ; range: 23.2-105.0 mg/week) genotype as compared to patients with CYP2C9*1/*2 (median dose: 31.5 mg/week ; range: 10.5-46.5 mg/week) and CYP2C9*1/*3 genotype (median dose: 23.6 mg/week ; range: 9.0-63.0 mg/week). For patients with subtherapeutic INR values median weekly dose was 40.5 mg in patients with CYP2C9*1/*1 genotype, 30.7 mg in patients with CYP2C9*1/*2 genotype and 16.1 mg in patients with CYP2C9*1/*3 genotype. 9 out of 10 patients with INR values <1.5 were homozygous for the CYP2C9*1 allele, and the median weekly dose was 26.2 mg. As heterozigotes with polymorphic alleles require significantly lower doses to achieve the same anticoagulant effect as wild-type homozygotes, the analysis of CYP2C9 genotype could predict warfarin sensitivity.

P450 CYP2C9; warfarin; genetic polymorphism

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