Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors

Abstract

The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

“…[1][2][3]5,11,[20][21][22][23][24] Our subjects have previously been genotyped for CYP2C9, and the frequency of CYP2C9 homozygous extensive metabolisers was 66.7%, heterozygous extensive metabolisers 31.3% and poor metabolisers 2.0%. 3 The combined effect of VKORC1 and CYP2C9 on warfarin dose is presented in Figure 6, which shows that VKORC1 has a clear effect on all extensive metabolisers. In a multiple model, VKORC1, CYP2C9, age, bodyweight, interacting drugs, and indication for treatment together account for 56.0% of the total inter-individual variance in warfarin response ( Table 3).…”

“…It is well known that polymorphisms in CYP2C9 are associated with warfarin sensitivity. 3 An Italian group lead by Margaglione recently described an association between warfarin dose and genotypes of CYP2C9 and two noncoding VKORC1 SNPs (rs9934438 and rs7294) in 147 patients. 41 In their study, CYP2C9 and VKORC1 together account for 35% of interindividual variability.…”

“…1 It is used in atrial fibrillation, recurrent stroke, deep vein thrombosis, pulmonary embolism, and in patients with heart valve prosthesis. 2,3 The therapeutic response is possible to measure by the prothrombin time international normalised ratio (PT INR); 4 nevertheless, warfarin is difficult to handle because of a narrow therapeutic range and a 20-fold inter-individual variation in dose requirement. 5,6 Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism.…”

“…11 Factors such as age, bodyweight, diet and concomitant medication are well known to affect dose requirement. 3,[12][13][14] Variation in warfarin pharmacokinetics is another important factor influencing dose. 15 Warfarin is administered as a racemate that consists of R-and S-enantiomers, the S-form being three to five times more active than the R form.…”

“…19 A large number of studies concerning the influence of CYP2C9 genotype on warfarin dose have been published. [1][2][3]5,11,[20][21][22][23][24] There is as yet limited information regarding pharmacodynamic factors involved in variable response to warfarin. Warfarin acts through interference with the vitamin K cycle in the liver (Figure 1).…”