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

Abstract

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.

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

“…This discrepancy could be due to the fact that CYP2C9 variant alleles are more frequent in the Italian population than in the Swedish. 1,41,42 In Margaglione's study, the allele frequencies of CYP2C9*2 and *3 were 17.0% and 8.8%, respectively, 41 as compared with our figures of 11.2% and 6.5%. 3 On the other hand, there was no major difference between populations in the frequency of the intragenic VKORC1 SNP rs9934438: MAF 39.8% in the Italians, and 38.8% in the Swedes.…”

“…Polymorphisms in the liver enzyme CYP2C9, which metabolises warfarin, are known to be associated with warfarin sensitivity. [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.…”

“…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.…”

“…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).…”

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

“…Among the 11 variant alleles of CYP2C9 so far reported, 7 CYP2C9*2 and CYP2C9*3 would be most important in the light of their influence on in vitro and in vivo metabolic activities and allelic frequencies in different ethnic populations. [8][9][10][11][12][13][14][15] CYP2C9*4 16 has been detected so far in only one Japanese patient whose phenytoin clearance was shown to be substantially reduced as compared with those possessing CYP2C9*1/*1. The allelic frequency of this variant should be very low in Japanese and no information is available in Caucasian and African-American populations.…”