KINETICS OF ANTICOAGULANT EFFECT OF DICUMAROL IN RATS

¹ Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York

The purposes of this study were 1) to determine the relationship between plasma-dicumarol concentration and anticoagulant effect in rats and 2) to compare the kinetics of the anticoagulant effect of dicumarol in the rat and man. Special methodology was developed for repeated determination of dicumarol concentration and prothrombin complex activity in individual animals. The inhibition of prothrombin complex activity synthesis rate at any time could be related quantitatively to the dicumarol concentration in the plasma. This permits a quantitative description of the time course of the anticoagulant effect in relation to the elimination kinetics of dicumarol. There are quantitative differences between rats and man in the pharmacokinetic constants for dicumarol elimination, for synthesis and degradation of vitamin K-dependent clotting factors as reflected by prothrombin complex activity and for the relationship between drug concentration and effect, but the pharmacokinetic relationships are basically the same. Consequently, the rat can be a useful animal model for studying various drug interactions and other factors which modify the activity of coumarin anticoagulants.