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.

Metabolism of tritium- and carbon-14-labeled tiamulin in dogs, rats, and pigs.

The metabolism of tiamulin hydrogen fumarate, labeled with 3H, 14C, or both, was studied in dogs, rats, and weanling pigs. After a dose of radiolabeled tiamulin, all three species excreted more radioactivity in feces (via bile) than in urine. Dogs absorbed 86% of a single oral dose of tiamulin-3H, and the disposition of the compound was similar after a single or multiple dosage regimen. The ratio of antimicrobial activity to total radioactivity in dog plasma was only about 0.25, and was still less in dog urine. After dosing with tiamulin-14C, rats and pigs excreted at least 1% of the dose as 14CO2 in expired air. In dual-labeled studies, pigs excreted less total 14C than 3H and had greater residues of 14C than 3H in edible tissues, blood, and plasma. After the administration of tiamulin-14C to pigs, radioactivity was incorporated into liver glycogen, indicating metabolic cleavage of the side chain of tiamulin. Tiamulin-3H is the isotopically-labeled compound of choice for studying metabolism and tissue residues in animals.