RELATIONSHIP BETWEEN DISTRIBUTION, ELIMINATION AND ANTICOAGULANT ACTION OF DICUMAROL

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

The purpose of this investigation was to determine the relationship between the distribution, elimination and anticoagulant action of dicumarol and thereby to obtain a better understanding of the clinical implications of the large intersubject differences in the biologic half-life of dicumarol in healthy human subjects not receiving other drugs. It was found that the serum/liver concentration ratio of dicumarol in rats which eliminated the drug rapidly was lower than in animals which eliminated dicumarol more slowly. When the apparent first-order elimination rate constants for dicumarol were corrected for individual differences in distribution of the drug between the liver (the site of biotransformation) and the rest of the body, the intersubject differences in climination rate constants practically disappeared. It was also found that rats with widely different half-lives of dicumarol differed with respect to the relationship between plasma concentration of dicumarol and intensity of anticoagulant effect. A given plasma concentration of dicumarol produced a more pronounced anticoagulant effect in rapid eliminators of the drug. Consequently, the intersubject differences in time course of prothrombin complex activity were not as pronounced as the differences in either the half-life of dicumarol or in the drug concentration-anticoagulant response relationship.