Influence of the intestinal microflora on the elimination of warfarin in the rat

The effect of the intestinal microflora on the half-life and elimination of warfarin in rats was examined. When the intestinal microflora was reduced with neomycin, bacitracin, and tetracycline, or was nonexistent as in germ-free animals, more radioactivity was found in feces and less in the urine after ip administration of (14)C-warfarin. The ratio of conjugated to free metabolites in the feces was higher in germ-free rats compared to conventional or ex-germ-free animals. In addition, fecal β-glucuronidase levels were markedly decreased in antibiotic-treated rats and in germ-free rats when compared to conventional and ex-germ-free rats. In a crossover study, a 30% decrease in warfarin half-life was observed in germ-free and antibiotic-treated animals compared to the same rats in an ex-germ-free state. The antibiotic treatment, however, had effects other than reduction of the microflora. A significant decrease in the volume of distribution of warfarin was noted in antibiotic-treated animals which may invalidate the use of this widely used mixture as a model which may invalidate the use of this widely used mixture as a model for the study of intestinal microflora-drug interactions. To confirm enterohepatic recycling of warfarin, bile from donor rats administered (14)C-warfarin ip was infused into the upper duodenum of recipient rats. Bile from the recipient rats was shown to contain 0.1-0.9% of the radioactivity administered to the donor rats. At 6-8 hr after injection, serum of the recipient rats contained 2-10% of the radioactivity present in the serum from donor rats, and contained mainly free warfarin. These data are consistent with an important role for the intestinal microflora in facilitating enterohepatic recycling of warfarin in the rat.