Formation of a defluorinated metabolite of a quinoxaline antiviral drug catalysed by human cytochrome P450 1A2

The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihyd ro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug fo r the potential treatment of HIV, has been studied with singly expressed hu man cytochromes P450 (CYP 450). No biotransformation of [C-14]GW420867X was evident in the presence of any of the CYP 450 isoforms, with the exception of CYP 450 1A2, where a single metabolite was observed in the HPLC radioch romatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy a nd mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared th at CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumab ly during formation of an arene oxide intermediate during aromatic hydroxyl ation.