Jantoven® Tablets (Warfarin Sodium Tablets, USP) and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4 - 6 hours, IX - 24 hours, and X - 48 - 72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K₁ epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.

An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of Jantoven® Tablets may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

Pharmacokinetics

Jantoven® Tablets are a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2 - 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Absorption

Jantoven® Tablets are essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

Distribution

There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Jantoven® Tablets are stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolities (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4¹-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18,1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

Excretion

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