Urinary metabolites of a novel quinoxaline non-nucleoside 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-quinoxalinecarboxylic 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-preparative HPLC, NMR and LC-MS/MS. The relative proportions of fluorine-containing metabolites were determined for each species by 19F-NMR signal integration. 3. The metabolite profiles for each species were similar, although the proportion of individual components varied, suggesting that similar metabolic pathways are involved in the biotransformation of GW420867X in the species studied. 4. The urinary metabolites indicated that the major routes of biotransformation included hydroxylation and subsequent glucuronic acid conjugation on the aromatic ring, and on the ethyl and isopropyl side chains. A component was observed in mini-pig urine that corresponded to hydroxylation and glucuronidation accompanied by loss of the fluorine atom.
Ismail
I M
IM
International Development BioMet, Glaxo Wellcome Research and Development, UK. imi2682@glaxo wellcome.co.uk
Dear
G J
GJ
Mutch
P J
PJ
Davies
L H
LH
Plumb
R S
RS
Sweatman
B C
BC
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D011810:Quinoxalines / Q000652:urine*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000652:urine*; D013045:Species Specificity; D013552:Swine
C402066:GW420867X; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors