1. The urinary metabolites of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) have been investigated in samples obtained following oral administration to rabbit, mouse and human. GW420867X underwent extensive biotransformation to form hydroxylated metabolites and glucuronide conjugates on the aromatic ring, and on the ethyl and isopropyl side-chains in all species. In rabbit urine, a minor metabolite was detected and characterized as a cysteine adduct that was not observed in mouse or man. 2. The hydroxylated metabolites and corresponding glucuronide conjugates were isolated by semi-preparative HPLC and characterized using NMR, LC-NMR and LC-MS/MS. The relative proportions of fluorine-containing metabolites were determined in animal species by 19F-NMR signal integration. 3. The fluorine atom of the aromatic ring underwent NIH shift rearrangement in the metabolites isolated and characterized in rabbit, mouse and human urine. 4. The characterization of the NIH shift metabolites in urine enabled the detection and confirmation of the presence of these metabolites in human plasma.

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High‐performance liquid chromatography, nuclear magnetic resonance (NMR) spectroscopy and sequential mass spectrometry (MSn) have been combined to allow rapid and effective identification of metabolites in urine following administration of the novel non‐nucleoside reverse transcriptase inhibitor, GW420867. The combination of these techniques has enabled structural and molecular weight information to be interpreted by the analyst with greater efficiency and accuracy. This work demonstrates the potential of coupling MSn using an ion trap spectrometer with NMR spectroscopy, providing an extremely powerful technique for structural elucidation. Copyright © 1998 John Wiley & Sons, Ltd.

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