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Abstract

Oral administration to mice of high doses of 4-isothiocyano-4′nitrodiphenylamine (amoscanate), a potent antischistosomal drug, produced focal necrotizing lesions of the large intrahepatic and extrahepatic bile ducts and the gallbladder. Coadministration of erythromycin and, to a somewhat lesser degree, of paromomycin, markedly reduced the effects of amoscanate on the biliary tract. These results suggest that amoscanate may be converted to a cholangiotoxic product by one or several constituents of the enteric bacterial flora. Since erythromycin does not affect the antischistosomal activity of amoscanate, coadministration of an antibacterial agent can reduce toxic effects of a drug while full chemotherapeutic activity is maintained. The possibility of toxic effects of metabolites of xenobioties produced by intestinal bacteria deserves attention and the experimental production of focal intrahepatic and extrahepatic cholangitis by such drug metabolites suggests a possible mechanism in human bile diseases.