ACETAMIDE - METABOLITE OF METRONIDAZOLE FORMED BY THE INTESTINAL FLORA

Metronidazole is metabolized to acetamide in yields of between 8 and 15 per cent by cultures of rat cecal contents or Clostridium perfringens. The yield of acetamide is 6- to 9-fold greater than that of N-(2-hydroxyethyl)-oxamic acid which is also derived from metronidazole. When [2-14C] metronidazole is administered by gavage to conventional rats, 1.3 to 1.8 per cent of a 200 mg/kg dose is recovered as acetamide in the urine. An additional 0.9 to 2.4 per cent is recovered as acetamide in the feces. Acetamide is not detected, however, in either urine or feces when metronidazole is administered to germfree rats. The appearance of acetamide derived from metronidazole in conventional rats appears to be mediated by the intestinal microflora. The cleavage of the imidazole ring of metronidazole to yield both acetamide and N-(2-hydroxyethyl)-oxamic acid is consistent with nucleophilic attack at carbons 2 and 4 of a partially reduced nitroimidazole ring, which is then cleaved between positions 1 and 2 and between positions 3 and 4. Since acetamide has been shown previously to be a liver carcinogen for rats, its presence in the urine and the feces should be considered, together with other indirect evidence, when determining the possible risk of cancer to patients given metronidazole. © 1979.