The effect of broad-spectrum antibiotics on warfarin excretion and metabolism in the rat

The excretion and metabolism of ¹⁴C-warfarin in rats was examined in a crossover experiment, the first phase consisting of treatment with normal saline, the second phase using the same animals given neomycin, bacitracin, and tetracycline orally. Urine and feces were collected every 24 hours for 72 hours and examined for warfarin and its metabolites, both unconjugated and conjugated. Significantly more radioactivity was eliminated in the feces of antibiotic-treated rats. The feces of antibiotic-treated rats contained only trace amounts of β-glucuronidase activity. Urine contained a similar ratio of unconjugated to conjugated radioactivity in both treatment groups, but the antibiotic-treated animals had significantly larger amount of conjugates in their feces. Examination of metabolic profiles of conjugated and unconjugated fractions revealed significantly fewer hydroxylated metabolites in antibiotic-treated rats, especially in the feces. The lower amount of hydroxylative metabolism is attributed to a reduction in gut flora-mediated enterohepatic recycling caused by the antibiotics.