Determination of plasma warfarin concentrations in Korean patients and its potential for clinical application.

BACKGROUND: Warfarin is a widely used oral anticoagulant with broad within- and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice. METHODS: We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations. RESULTS: The mean maintenance dose of warfarin in 105 patients was 4.1 +/-1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3+/-0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r(2)=0.259, P<0.001) was higher than that with INR (r(2)=0.029, P=0.072). CONCLUSIONS: There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment.

Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients.

INTRODUCTION: Warfarin, a commonly prescribed anticoagulant, exhibits large interindividual and interethnic differences in the dose required for its anticoagulation effect. Asian patients require a much lower maintenance dose compared with Caucasians; the explanation for these differences remains unknown. METHODS: We analyzed five single nucleotide polymorphisms of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) and the *3 variant of cytochrome P450 (CYP)2C9, as well as the plasma warfarin concentration, in 108 Korean patients with atrial fibrillation. RESULTS: Genotypic frequencies of VKORC1 +1173CT and CYP2C9*1/*3 were 17.6 and 10.2%, respectively, in the study population; VKORC1 +1173CC and CYP2C9*3/*4 were detected in one patient each. Patients carrying at least one copy of the VKORC1 +1173C allele, or the H7 (group B) haplotype, required a significantly higher warfarin dose (n = 20; 5.5 +/- 1.7 mg/day) than those homozygous for the +1173T allele, or the H1 (group A) haplotype, (3.8 +/- 1.2 mg/day; p < 0.001). There were statistically significant differences in warfarin dose between the CYP2C9*1/*1 (4.3 +/- 1.6 mg/day; p < 0.001) and those with the other two genotypes including CYP2C9*1/*3 and CYP2C9*3/*4 (2.7 +/- 0.9 mg/day). The multiple regression analysis revealed that the VKORC1 genotype (r2 = 0.197; p < 0.001), the age when warfarin started (r2 = 0.09; p < 0.001), body surface area (r2 = 0.041; p = 0.004) and CYP2C9 genotype (r2 = 0.029; p = 0.014) were factors associated with the daily dose of warfarin required. CONCLUSION: In the present study, we found that the VKORC1 polymorphism had a dominant genetic influence on interindividual variability for warfarin dose in Korean patients. It explained approximately 32% of the overall variability in warfarin dose requirements given all of the variables studied. Thus, analysis of the VKORC1 genotypes may be important to guide warfarin dose selection and allow personalized warfarin treatment.