Coumadin - Clinical Pharmacology

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Absorption:

COUMADIN is essentially completely absorbed after oral administration with peak concentration gen-erally attained within the first 4 hours.

Distribution:

There are no differences in the apparent volumes of distribution after intravenous and oral adminis-tration 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 bioavailabil-ity, estimates of the volumes of distribution of R-and S-warfarin are similar to each other and to that of the race-mate. 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. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal antico-agulant 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, .4-, 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:

The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recov-ered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.