FORMATION OF A MUTAGENIC DRUG METABOLITE BY INTESTINAL MICROORGANISMS

  • 1 January 1978
    • journal article
    • research article
    • Vol. 38  (3) , 608-612
Abstract
A new broad-spectrum antiparasitic agent, 4-isothiocyano-4''-nitrodiphenylamine, is devoid of mutagenic activity in vitro, alone or in the presence of activating enzymes of rat liver, in Salmonella typhimurium. Six species of mammals receiving this drug excrete an as yet unidentified mutagenic metabolite. Several observations suggested that 1 or several constituents of the enteric bacterial flora, rather than the metabolic activities of the host, are involved in the formation of this mutagen. Unequivocal demonstration for such a mechanism was provided by germ free rats that do not form this metabolite, in contrast to their conventional littermates. Only a relatively moderate and apparently selective reduction in the total number of microorganisms of the intestinal flora is needed to eliminate this mutagenic transformation. Following administration of a single dose of erythromycin or erythromycylamine, conversion of the isothiocyanate to a mutagen can be prevented completely, while antiparasitic activity is maintained. There is no obligatory association between chemotherapeutic activity and the formation of the mutagenic metabolite and these 2 activities can be dissociated completely. This suggests a new approach for increasing the safety of pharmacological agents.