LY255582 is a phenylpiperidine opioid antagonist under development as
an appetite suppressant and for the treatment of obesity, Female beagl
es were administered [C-14]LY255582 at dosages of 0.72 mg/kg intraveno
usly or 7.2 mg/kg orally. The majority (54-58%) of the radioactivity w
as eliminated in the urine over 8 days after both oral and intravenous
drug administration, primarily as polar metabolites, Peak plasma leve
ls of parent drug in the dog were 11.5 and 311 ng/ml after oral and in
travenous 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 [C-14]LY255582 at dosages of 35 mg/kg or
ally and 1 mg/kg intravenously, respectively. The half-life of parent
drug in rats was 1.5 hr; however, the terminal half-lives of radioacti
vity equivalents were 7.9 and 31.7 hr after intravenous and oral admin
istration, respectively, The bioavailability of parent LY255582 was <1
% in both the rat and the dog, primarily because of extensive first-pa
ss metabolism, Whole-body autoradiographic studies in rats after admin
istration of a single oral 35 mg/kg dose of [C-14]LY255582 indicated t
hat radioactivity was rapidly absorbed and distributed throughout the
body, Radioactivity concentrated in the liver and was eliminated slowl
y, Little or no parent drug was eliminated in the urine of either spec
ies, As in the urine, the major residues present in the liver and bile
of rats orally administered [C-14]LY255582 were uncharacterized polar
metabolites with little parent drug present.