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Influence of the intestinal microflora on the elimination of warfarin in the rat
Abstract:
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 14C-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 beta-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 for the study of intestinal microflora-drug interactions. To confirm enterohepatic recycling of warfarin, bile from donor rats administered 14C-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.
Insights
Intestinal microflora significantly impacts warfarin elimination in rats by influencing enterohepatic recycling. Reducing gut bacteria shortens warfarin
Area of Science:
- Pharmacology
- Microbiology
- Drug Metabolism
Background:
- Warfarin is a widely used anticoagulant.
- The role of intestinal microflora in drug metabolism is increasingly recognized.
- Enterohepatic recycling can affect drug half-life and efficacy.
Purpose of the Study:
- To investigate the influence of intestinal microflora on warfarin's pharmacokinetics in rats.
- To determine the impact of microflora reduction on warfarin elimination and metabolism.
- To confirm the role of enterohepatic recycling in warfarin's disposition.
Main Methods:
- Administration of 14C-warfarin to conventional, antibiotic-treated, and germ-free rats.
- Measurement of radioactivity in feces and urine.
- Analysis of warfarin metabolites.
- Bile infusion studies to assess enterohepatic recycling.
- Crossover study comparing warfarin half-life in different microflora states.
Main Results:
- Reduced intestinal microflora led to increased fecal excretion and decreased urinary excretion of warfarin metabolites.
- Germ-free and antibiotic-treated rats exhibited a 30% shorter warfarin half-life.
- Fecal beta-glucuronidase levels were decreased in rats with reduced microflora.
- Antibiotic treatment also decreased the volume of distribution of warfarin.
- Bile infusion confirmed enterohepatic recycling of warfarin in rats.
Conclusions:
- Intestinal microflora plays a crucial role in facilitating enterohepatic recycling of warfarin in rats.
- Microflora-mediated recycling significantly influences warfarin's half-life and elimination.
- Antibiotic-induced alterations in gut bacteria and other factors affect warfarin pharmacokinetics.