Abstract
Background The warfarin sensitivity index (WSId)= INR/warfarin dose, is mainly determined by pharmacokinetic factors (CYP 2C9 genotype and age). WSIc (INR/plasma warfarin concentration) should reflect the influence of pharmacodynamic factors. We examined the effect on WSIc of polymorphisms in genes coding the enzymes of the vitamin K dependent γ-carboxylation system, together with oxidative stress markers (given the putative antioxidant activity of the vitamin K cycle). Patients and Methods We quantified the effects of polymorphisms in the genes: γ-glutamyl-carboxylase (GGCX; G8762A), in two putative components of vitamin K epoxide reductase (VKOR): microsomal epoxide hydrolase (mEH; T612C) and glutathione S-transferase (GST A1; T567G) and in CYP 2C9, as well as of oxidative stress markers (GSH/GSSG) on WSIc in 100 patients at stable anticoagulation. Results On multiple regression WSId was solely associated with pharmacokinetic factors: age (r2=0.07), CYP 2C9 genotype (r2=0.14) and plasma warfarin concentrations (r2=0.07). WSIc was significantly associated with GGCX genotype (r2=0.07), CYP 2C9 genotype (r2=0.04) and oxidative stress status (GSH/GSSG) (r2=0.04) with no effect of concomitant drugs, age or weight. Conclusions Individual sensitivity to warfarin, adjusted for plasma concentrations (WSIc) is determined by GGCX genotype and oxidative stress status, beyond the known effects of age and CYP2C9. Clinical Pharmacology & Therapeutics (2005) 77, P96–P96; doi: 10.1016/j.clpt.2004.12.261
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