Pharmacology of Warfarin

After oral administration, warfarin is completely absorbed, and then 99% of it is bound to albumin in the plasma. Warfarin, which is free, is taken up by the liver where it is biologically active and metabolized by the cytochrome P450 complex (CYP2C9). Commercially available warfarin (Coumadin™ and others) is a racemic mixture with each of the two enantiomers having its own route of metabolism (Fig. 1). The S-enantiomer is converted to 6- and 7-hydroxywarfarin by CYP2C9 and eventually excreted in the bile, whereas the R-enantiomer is metabolized by CYP1A1, CYP1A2, and CYP3A4 to an inactive alcohol that is excreted in the urine (7). The S-enantiomer more strongly blocks the regeneration of the reduced form of vitamin K, thereby interfering with the vitamin K-dependent carboxylation of glutamic acid residues on coagulation factors prothrombin II, VII, IX, and X. Although warfarin also inhibits the synthesis of the anticoagulant proteins C, S, and Z, its pharmacologic effect is inhibition of the synthesis of functional clotting factors.

Figure 1 After oral absorption, warfarin is transported to the liver, where CYP1A1, CYP1A2, and CYP3A4 metabolize the R-enantiomer and CYP2C9 metabolizes the more potent S-enantiomer. By impairing the regeneration of the reduced form of vitamin K, R- and S-warfarin interfere with the vitamin K-dependent carboxylation of clotting factors prothrombin VII, IX, and X.

Figure 1 After oral absorption, warfarin is transported to the liver, where CYP1A1, CYP1A2, and CYP3A4 metabolize the R-enantiomer and CYP2C9 metabolizes the more potent S-enantiomer. By impairing the regeneration of the reduced form of vitamin K, R- and S-warfarin interfere with the vitamin K-dependent carboxylation of clotting factors prothrombin VII, IX, and X.

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