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‐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...

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Bibliographic Details
Published in:	Journal of pharmacy and pharmacology Vol. 53; no. 3; pp. 403 - 408
Main Authors:	Mutch, Peter J., Dear, Gordon J., Ismail, Issy M.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-03-2001 Pharmaceutical Press
Subjects:	Anti-HIV Agents - pharmacokinetics Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - pharmacokinetics Biological and medical sciences Biotransformation Chromatography, High Pressure Liquid Cytochrome P-450 CYP1A2 - metabolism Half-Life Human immunodeficiency virus Humans In Vitro Techniques Isoenzymes - metabolism Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences Microsomes, Liver - enzymology Pharmacology. Drug treatments Quinoxalines - pharmacokinetics Human Quinoxaline derivatives Isozyme Metabolite Cytochrome P450 Retroviridae Metabolism Lentivirus Defluorination Virus Antiviral Human immunodeficiency virus Structural analysis
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Summary:	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.
Bibliography:	ArticleID:JPHP1150 ark:/67375/WNG-ZJTJ9NX6-K istex:A262BA033BC8FFCB4CEBE9D12A4766E6E8CBE81E ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3573 2042-7158
DOI:	10.1211/0022357011775479