Fig. 3 |. Sites of action for pharmacogenes involved in the response to warfarin.

The more potent S-enantiomer of warfarin is metabolized by the cytochrome P450 (CYP) 2C9 enzyme to the inactive 7-OH warfarin protein. Warfarin exerts its anticoagulation effects by inhibiting vitamin K oxidoreductase complex 1 (VKORC1), thereby preventing reduction of vitamin K epoxide to vitamin K₁, which is subsequently reduced to vitamin KH₂, a necessary cofactor for γ-carboxylation and activation of clotting factors II, VII, IX and X. The CYP4F2 enzyme metabolizes vitamin K₁ to an inactive hydroxyl-vitamin K₁ metabolite so that less is available for reduction to vitamin KH₂. Polymorphisms in the genes encoding the CYP2C9, VKORC1 and CYP4F2 proteins can affect warfarin metabolism, sensitivity to warfarin and vitamin K availability, respectively, thereby influencing warfarin dose requirements and bleeding risk. GGCX, γ-glutamyl carboxylase.