Abstract

GSK977779 is a potent HM74a agonist evaluated for the treatment of dyslipidemia. The disposition and metabolism of [¹⁴C]GSK977779 (67.6 μmol/kg p.o.) was studied in male and female rats. The compound was well absorbed and its primary route of elimination was in the feces. Based on metabolite profiling of plasma extracts and urine and bile samples, it was demonstrated that GSK977779 was extensively metabolized in the rat by N-dealkylation, mono- and dioxygenation, reductive and oxidative cleavage of the 1,2,4-oxadiazole ring, and conjugative pathways. After plasma extraction high amounts of nonextractable radioactivity were observed, which were more pronounced in female rats. Size-exclusion chromatography and SDS gel electrophoresis indicated that the majority of the nonextractable radioactivity was covalently bound to plasma proteins. Solubilization of the plasma protein pellet followed by high-performance liquid chromatography and mass spectrometry suggested that a carboxylic acid metabolite derived from oxadiazole ring cleavage may be responsible for the observed covalent binding of the radioactivity to rat plasma proteins.