Studies on the Metabolic Fate of Amrubicin Hydrochloride (SM-5887), a Novel Antitumor Agent. (IV): Metabolism of SM-5887 in Rats and Dogs.

Abstract

The metabolism of amrubicin hydrochloride (SM-5887), a novel antitumor agent, was investigated in rats and dogs after intravenous administration of 14C-labeled SM-5887. 1. Nine metabolites in rat urine, ten metabolites in rat bile, six metabolites in dog urine and eleven metabolites in dog bile were observed after intravenous administration of 14C-SM-5887. Major radioactive components in rat urine were amrubicinol (SM-5887-13-OH) and the unchanged SM-5887, and those in dog urine were M-2 and Met B. Major radioactive components in bile of rats and dogs were polar metabolites, such as M-1 and M-2. 2. In rat tissues, ma jor radioactive components were nonpolar or less polar metabolites, such as Met B and SM-5887-13-OH, and the unchanged SM-5887. 3. The structures of the nonpolar or less polar metabolites (SM-5887-13-OH and Met A ?? Met D) were determined by comparing them to the authentic samples using HPLC and mass spectrometry. The identified metabolites were an alcoholic derivative (SM-5887-13-OH), deoxyaglycones (Met A and Met B) formed by reductive glycosidic cleavage, an aglycone (Met B) formed by glycosidic cleavage and a deaminated derivative (Met D). Two polar metabolites (M-4 and M-6) were also identified as the conjugates of SM-5887-13-OH with glucuronic acid. The other polar metabolites (M-1 ?? M-3, M-5 and M-7), which were assumed to be conjugates based on their high polarities, could not be identified due to their low stabilities.