The Biochemistry of Warfarin Action

This is a complex biochemical and medical subject, certainly beyond the simple chemistry required for a molecule of the month! Warfarin acts as a Vitamin K antagonist, that is it blocks the action of vitamin K epoxide reductase.

Vitamins K₁ and K₂

This vitamin is found in brassicas, spinach, parsley, and other green vegetables, avocado pairs are also rich in Vitamin K₁.

For Vitamin K₂, n signifies a number of five-carbon side chain units, hence MK_-n, and except for MK₄, is synthesised by gut bacteria. Both vitamins are fat soluble, the "K" deriving from the German "koagulation". German researchers discovered the K vitamins, and that they are involved in blood clotting.

Vitamin K Cycle

Vitamin K is a cofactor in the synthesis of blood clotting factors II, VII, IX and X^*, this step occurs in the liver and involves the gamma carboxylation of the first 10 glutamic acid residues in the amino-terminal region of the prothrombin clotting factor to generate gamma-carboxyglutamate. The gamma-carboxyglutamatee amino acid groups can chelate Ca²⁺ better than ten replaced glutamate residues, thus providing binding sites for four Vitamin Ks onto the phospholipid membrane during coagulation. The clotting occurs via a cascade^*, a kind of biochemical chain reaction. {See Biochemistry by Stryer for the terminology}

To work, the Vitamin K must be reduced to its quinol or hydroquinone form. This is achieved with Vitamin K Oxide reductase, which is the step inhibited by S-warfarin, being some three times more potent than R-warfarin. S-warfarin is metabolized primarily by the CYP2C9 enzyme of the cytochrome P450 system. The R-warfarin is metabolized by the two cytochrome P450 enzymes, CP1A4Y and CYP3A4. Warfarin is very soluble in water, and is absorbed into the blood stream within 90 minutes of taking the pills.

So far as the enantiomers are concerned, racaemic warfarin has a half life of around 40 hours, the two enantiomers, having half lives: R-warfarin, 45 hours; S-warfarin, 29 hours.

During my review for MoTM, necessarily hurried, I have not been able to find out if the hemiketal, with the four enantiomers is involved. That the hemiketal is weak is shown by the crystal structure study, so, in any case these enantiomers will have short half lives. It all adds to the complexity.