Comparative Pharmacokinetics of Coumarin Anticoagulants V: Kinetics of Warfarin Elimination in the Rat, Dog, and Rhesus Monkey Compared to Man

Abstract

Small (1–4 mg./kg.) and large (10–12.5 mg./kg.) doses of sodium warfarin were administered intravenously to rats (Sprague-Dawley, male), dogs (mongrel, male), and monkeys (rhesus, male). Warfarin concentrations in the plasma declined exponentially with time in each species. The plasma half-life of warfarin was independent of dose in the dog, appears to decline slightly with increasing dose in the rat, and increases markedly with increasing dose in the monkey. Apparent volumes of distribution (dose/Cp0) increased slightly with increasing dose in most of the animals. The half-life of warfarin, as observed in this study, increases in the order: rat < monkey < dog < man. It is shown that the dose-dependent elimination kinetics of bishydroxycoumarin, known to occur in man and monkeys, can be observed also with the other widely used coumarin anticoagulant, warfarin, when sufficiently high doses of the latter are administered. This effect is not seen clinically perhop; because the therapeutic dose range of warfarin is much lower than that of bishydroxycoumarin. Concomitant administration of a large dose (≥10 mg.,/kg.) of bishydroxycoumarin with sodium warfarin (2 mg./kg.) to monkeys tended to increase the half-life of warfarin. These observations are consistent with other indications suggesting that the two coumarin anticoagulants are subject to the same major biotransformation pathway(s). Small (1–4 mg./kg.) and large (10–12.5 mg./kg.) doses of sodium warfarin were administered intravenously to rats (Sprague-Dawley, male), dogs (mongrel, male), and monkeys (rhesus, male). Warfarin concentrations in the plasma declined exponentially with time in each species. The plasma half-life of warfarin was independent of dose in the dog, appears to decline slightly with increasing dose in the rat, and increases markedly with increasing dose in the monkey. Apparent volumes of distribution (dose/Cp0) increased slightly with increasing dose in most of the animals. The half-life of warfarin, as observed in this study, increases in the order: rat < monkey < dog < man. It is shown that the dose-dependent elimination kinetics of bishydroxycoumarin, known to occur in man and monkeys, can be observed also with the other widely used coumarin anticoagulant, warfarin, when sufficiently high doses of the latter are administered. This effect is not seen clinically perhop; because the therapeutic dose range of warfarin is much lower than that of bishydroxycoumarin. Concomitant administration of a large dose (≥10 mg.,/kg.) of bishydroxycoumarin with sodium warfarin (2 mg./kg.) to monkeys tended to increase the half-life of warfarin. These observations are consistent with other indications suggesting that the two coumarin anticoagulants are subject to the same major biotransformation pathway(s).