Urinary metabolites of a novel quinoxaline nonnucleoside reverse transcriptase inhibitor in dog, cynomolgus monkey and mini-pig

1. The metabolism of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline- carboxylic acid isopropylester (GW420867X) has been investigated following oral administration to dog, cynomolgus monkey and mini-pig. 2. The urinary metabolites were isolated and characterized using semi-prepa rative HPLC, NMR and LC-MS/MS. The relative proportions of fluorine-contain ing metabolites were determined for each species by F-19-NMR signal integra tion. 3. The metabolite profiles for each species were similar, although the prop ortion of individual components varied, suggesting that similar metabolic p athways are involved in the biotransformation of GW420867X in the species s tudied. 4. The urinary metabolites indicated that the major routes of biotransforma tion included hydroxylation and subsequent glucuronic acid conjugation on t he aromatic ring, and on the ethyl and isopropyl side chains. A component w as observed in mini-pig urine that corresponded to hydroxylation and glucur onidation accompanied by loss of the fluorine atom.