@article {Tsaltadmd.110.036467, author = {Catherine D Tsalta and Armina Madatian and Ernest M Schubert and Fangming Xia and William M Hardesty and Yanli Deng and Jennifer L Seymour and Peter D Gorycki}, title = {Metabolsim of [14C]GSK977779 in Rats and its Implication with the Observed Covalent Binding}, elocation-id = {dmd.110.036467}, year = {2011}, doi = {10.1124/dmd.110.036467}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 with its primary route of elimination being in the feces. Based on metabolite profiling of plasma extracts, urine and bile samples, it was demonstrated that GSK977779 was extensively metabolized in the rat by N-dealkylation, mono- and di-oxygenation, reductive and oxidative cleavage of the 1, 2, 4-oxadiazole ring and conjugative pathways. Following plasma extraction high amounts of non-extractable radioactivity were observed which were more pronounced in female rats. Size-exclusion chromatography (SEC) and sodium dodecyl sulphate (SDS) gel electrophoresis indicated that the majority of the non-extractable radioactivity was covalently bound to plasma proteins. Solubilization of the plasma protein pellet followed by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) 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.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2011/05/31/dmd.110.036467}, eprint = {https://dmd.aspetjournals.org/content/early/2011/05/31/dmd.110.036467.full.pdf}, journal = {Drug Metabolism and Disposition} }