Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

“…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.…”

“…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

“…Recently, different groups of investigators have reported the relation between CYP2C9 polymorphisms (ie, CYP2C9*2 and CYP2C9*3) and the daily dose requirement of warfarin and risks of bleeding complications during anticoagulation therapy. [22][23][24][25][26][27][28][29][30][31][32] These studies support an idea that the genetic polymorphisms of CYP2C9 would contribute to the interindividual variability of the anticoagulation responses to warfarin along with the previously known clinical and environmental variables (eg, age, concomitantly administered drugs, foods and clinical indications). 33,34 Our knowledge about pharmacodynamic factors associated with the variability in the anticoagulation of warfarin is relatively limited.…”

“…Tables 1 and 2 summarize the data obtained from previous studies investigating the relation between the CYP2C9 genotypes and the maintenance daily dose of warfarin associated with therapeutic anticoagulation. Available data [22][23][24][25][26][27][28][29][30][31] agree with the notion that the stable maintenance dose of warfarin would differ significantly among the patients possessing distinct CYP2C9 genotypes and that the magnitude of impact by CYP2C9*3 variant on the dose requirement of warfarin would be greater than that by CYP2C9*2 variant.…”

“…In addition, we wish to give a comprehensive pharmacokinetic explanation why the patients carrying genetic polymorphisms associated with reduced CYP2C9 activity would have less stable INR status than those with the wild-type genotype particularly during the initial phase of warfarin therapy. 22 were the first to report that patients with CYP2C9*2 allele required 20% lower maintenance dose of warfarin than those with the wildtype (CYP2C9*1) allele. Recently, Aithal et al 23 reported that patients requiring a lower dose of warfarin (ie, o1.5 mg/day) to maintain optimum anticoagulation had a higher incidence (81%) of having one or more CYP2C9 variant alleles (ie, CYP2C9*2 and CYP2C9*3) than those randomly selected from anticoagulation clinics (38%).…”