Studies in rats on the mechanism by which 6-mercaptopurine inhibits the anticoagulant effect of warfarin.

The observation in man that 6-mercaptopurine (6-MP) decreases the anticoagulant effect of warfarin could be simulated in male Wistar Lewis rats. This permitted a detailed study in animals on the mechanism of this drug interaction. It was found that 6-MP treatment (5 mg/kg at 12-hour dose intervals) neither affects the distribution nor increases the elimination rate of 14C-warfarin. The degradation rate of prothrombin complex activity (determined after blocking the synthesis of prothrombin complex activity by 15 mg/kg of warfarin sodium) was also not inhibited by 6-MP. When added to rat plasma in vitro, 6-MP had no effect on prothrombin times. It was evident, however, that 6-MP treatment produces a significant shortening of the prothrombin times of nonanticoagulated animals. This effect was completely reversible a few days after discontinuance of 6-MP treatment. Analysis of the activity of clotting factors II, V, VII, VIII, and X by one-stage assays using human deficient substrate plasma revealed that the increase in prothrombin complex activity during 6-MP treatment is mainly due to an increase in factor II activity. From these experiments it appears that 6-MP increases the synthesis and/or activation of prothrombin and thereby decreases the response to oral anticoagulant drugs.