TABLE 1: Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients *
SD = Standard deviation.
†
p < 0.001. Pairwise comparisons indicated significant differences among all 3 genotypes.
CYP2C9 Genotype N S-Warfarin Clearance/Lean Body Weight
(mL/min/kg)
Mean (SD)*
*1/*1 118 0.065 (0.025)†
*1/*2 or *1/*3 59 0.041 (0.021)†
*2/*2, *2/*3 or *3/*3 11 0.020 (0.011)†
Total 188 

Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6 and *11 alleles in populations of African ancestry and *5, *9 and *11 alleles in Caucasians.

Excretion
The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Pharmacogenomics
A meta-analysis of nine qualified studies including 2,775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.3 In this meta-analysis, three studies assessed bleeding risks and eight studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study, the risk of achieving INR > 3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR > 3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.4

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G > A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.5 About 55% of the variability in warfa