Formation of a defluorinated metabolite of a quinoxaline antiviral drug catalysed by human cytochrome P450 1A2
- 1 March 2001
- journal article
- Published by Oxford University Press (OUP) in Journal of Pharmacy and Pharmacology
- Vol. 53 (3), 403-408
- https://doi.org/10.1211/0022357011775479
Abstract
The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug for the potential treatment of HIV, has been studied with singly expressed human cytochromes P450 (CYP 450). No biotransformation of [14C]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 radiochromatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy and mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared that CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumably during formation of an arene oxide intermediate during aromatic hydroxylation.Keywords
This publication has 9 references indexed in Scilit:
- Urinary metabolites of a novel quinoxaline non-nucleoside reverse transcriptase inhibitor in rabbit, mouse and human: identification of fluorine NIH shift metabolites using NMR and tandem MSXenobiotica, 2000
- Quantitative studies on the urinary metabolic fate of 2-chloro-4-trifluoromethylaniline in the rat using 19F-NMR spectroscopy and directly coupled HPLCNMR-MSXenobiotica, 1999
- Urinary metabolites of a novel quinoxaline non-nucleoside reverse transcriptase inhibitor in dog, cynomolgus monkey and mini-pigXenobiotica, 1999
- Distal Site and Surface Mutations of Cytochrome P450 1A2 Markedly Enhance Dehalogenation of Chlorinated HydrocarbonsArchives of Biochemistry and Biophysics, 1997
- NIH shift in the hydroxylation of aromatic compounds by the ammonia-oxidizing bacterium Nitrosomonas europaea. Evidence against an arene oxide intermediateBiochemistry, 1995
- Metabolism of sertindole: identification of the metabolites in the rat and dog, and species comparison of liver microsomal metabolismXenobiotica, 1995
- Identification of Cytochrome P450 2E1 as the Predominant Enzyme Catalyzing Human Liver Microsomal Defluorination of Sevoflurane, Isoflurane, and MethoxyfluraneAnesthesiology, 1993
- Application of19F.n.m.r. spectroscopy to the identification of dog urinary metabolites of imirestat, a spirohydantoin aldose reductase inhibitorXenobiotica, 1992