Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance

Objective: Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance. Methods: The study population consisted of 93 Italian outpatients receiving long-term warfarin anticoagulant therapy (international normalized ratio values, 2-3), divided into 3 dose groups: low (<26.25 mg/wk; n=37), medium (26.25-43.75 mg/wk, n=32), and high (>43.75 mg/wk; n=24). Steady-state unbound plasma concentrations of S- and R-warfarin were measured by HPLC and equilibrium dialysis, and corresponding unbound oral clearance (CLfree) values were calculated. Allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) and CYP2C19 (CYP2C19*2) were identified by polymerase chain reaction, followed by restriction enzyme analysis. Results: Fifty-four patients carried no CYP2C9 mutated alleles (*1/*1), 31 carried one (*1/*2, n=15; and *1/*3, n=16), and 8 carried two (*2/*2, n=2; *3/*3, n=2; and *2/*3, n=4). Two subjects were homozygous and 19 were heterozygous for the CYP2C19*2 allele variant. The frequencies of CYP2C9 mutated alleles were 72% in the low-dose group, 36% in the medium-dose group, and 4% in the high-dose group; the corresponding mean S-warfarin CLfree values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S-warfarin CLfree values varied significantly among the CYP2C9 genotype groups (P<.0001), although most patients (72%) with no mutated alleles showed S-warfarin CLfree values in the same range as those carrying mutated alleles (58-777 mL/min). No relationship was found between S-warfarin CLfree and CYP2C19 genotype or between R-warfarin CLfree and either CYP2C9 or CYP2C19 genotype. Conclusion: CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S-warfarin enantiomer, although nongenetic factors may also contribute to their large interindividual variability.