Major routes of naftifine biotransformation in laboratory animals and man

Following dermal or oral administration to laboratory animals and man (E)-N-methyl-N-(1-naphthylmethyl)-3-phenyl-2-propen-1-amine- hydrochloride (naftifine), the antifungal constituent of Exoderil, is quantitatively biotransformed into, and excreted as metabolites devoid of antifungal activity. The structures of 15 metabolites were elucidated. In rat urine and bile these metabolites represent 70% of the orally absorbed dose. The biotransformation routes are: N-dealkylation, oxidation or reduction of the aldehyde intermediates from a) to the corresponding carboxylic acid- or alcohol-type metabolites, arene oxide formation in the phenyl- and naphthalene moieties of Naftifine, and conjugation, mainly with glucuronic acid and glycine. Similar metabolite patterns were obtained after oral and parenteral administration. The same pathways of naftifine biotransformation were observed in all species investigated, i.e. in man, rat, dog, rabbit and guinea pig, the last two species most closely resembling to man with respect to overall kinetics and urinary metabolite pattern.