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Abstract
The metabolism and disposition of LY368842, a β3-adrenergic receptor agonist, were characterized in F344 rats following oral or intravenous administration of [14C]LY368842. These studies were conducted as part of the investigation of the mechanism of dark liver pigmentation in LY368842-treated F344 rats. The maximum plasma concentration of LY368842 was reached at 3 h after an oral dose, with an elimination half-life of 4 h. The oral bioavailability of LY368842 was determined as 8%. A tissue distribution study by quantitative whole-body autoradiography indicated high concentrations of radiocarbon in gastrointestinal contents and moderate concentrations in liver. The radiocarbon was rapidly eliminated in rats, with approximately 3% of the dose recovered in urine and 90% in faeces over 168 h. In bile duct-cannulated rats, about 42% of the dose was recovered in bile and 41% remained in the faeces. Metabolites of LY368842 were identified in rat urine, faeces, bile and plasma samples. Oxidative metabolism of LY368842 led to the formation of a hydroxy metabolite, an indole-2,3-dione metabolite and oxidative cleavage products such as amine and diol metabolites. Several glucuronide conjugates were also identified in rat bile. These data suggest that LY368842 is not completely absorbed but is widely distributed, extensively metabolized and rapidly eliminated in rats after oral administration.