LY255582 is a phenylpiperidine opioid antagonist under development as an appetite suppressant and for the treatment of obesity. Female beagles were administered [14C]LY255582 at dosages of 0.72 mg/kg intravenously or 7.2 mg/kg orally. The majority (54-58%) of the radioactivity was eliminated in the urine over 8 days after both oral and intravenous drug administration, primarily as polar metabolites. Peak plasma levels of parent drug in the dog were 11.5 and 311 ng/ml after oral and intravenous administration, respectively, and declined with a half-life of 3.2 hr. Peak plasma levels of LY255582 in the rat were 7.9 and 160 ng/ml after administration of [14C]LY255582 at dosages of 35 mg/kg orally and 1 mg/kg intravenously, respectively. The half-life of parent drug in rats was 1.5 hr; however, the terminal half-lives of radioactivity equivalents were 7.9 and 31.7 hr after intravenous and oral administration, respectively. The bioavailability of parent LY255582 was < 1% in both the rat and the dog, primarily because of extensive first-pass metabolism. Whole-body autoradiographic studies in rats after administration of a single oral 35 mg/kg dose of [14C]LY255582 indicated that radioactivity was rapidly absorbed and distributed throughout the body. Radioactivity concentrated in the liver and was eliminated slowly. Little or no parent drug was eliminated in the urine of either species. As in the urine, the major residues present in the liver and bile of rats orally administered [14C]LY255582 were uncharacterized polar metabolites with little parent drug present.