Warfarin: metabolism and mode of action

The various stages involved in the transport, pharmacological action and elimination of warfarin involve the specific binding of warfarin to a chiral macromolecular complex. However, it seems that the degree of stereoselectivity is variable, which presumably reflects the importance of the side-chain in binding to each type of macromolecule. It would appear that there is greater stereoselective control in the interaction of warfarin with cytochrome P-450 enzymes than that observed for interaction with the receptor, vitamin K1 epoxide reductase. Indeed, warfarin has been developed as a powerful stereochemical probe for in vitro studies of the terminal enzyme in the mixed-function oxidase system, cytochrome P-450. Warfarin undergoes hydroxylation in the 6, 7 and 8-positions of the aromatic ring which must interact with the active (haemoprotein) portion of the molecule, leaving the side-chain, which contains the chiral centre, free for recognition by the substrate binding site. In vitro studies indicate that the interaction of warfarin at its receptor, vitamin K1 epoxide reductase, is completely non-stereoselective. This suggests that only the 4-hydroxycoumarin ring portion of the drug binds to the enzyme. Consistent with this hypothesis, salicylate, which can mimic part of the 4-hydroxycoumarin ring system, produces hypothrombinaemia by inhibition of vitamin K1 epoxide reductase. These findings suggest that the coumarin ring system is largely responsible for the pharmacodynamic properties of warfarin, whereas the side-chain dictates the disposition and metabolism of the drug.