title: Oxidative biotransformation of oxazepam to reactive and nonreactive products in rat, mouse and human microsomes.
abstract: 1. The oxidative metabolism of oxazepam by human, B6C3F1 mouse and F344 rat microsomes was examined. The major metabolite in all three species was 6-chloro-4-phenyl-2(1H)-quinazolinecarboxylic acid (CPQ-carboxylic acid). In addition, rat microsomes produced 4'-hydroxyoxazepam and oxazepam-dihydrodiol in NADPH-containing incubations. 2. Covalent protein adducts were increased by the addition of NADPH to rat and mouse microsomes but not human microsomes. The magnitude of adduct formation was rats > mice > humans. 3. Formation of oxazepam-dihydrodiol was reduced by the addition of cyclohexene oxide and GSH to the incubations. Two additional metabolites were produced under these conditions. One of these was tentatively identified as a GSH conjugate. Covalent adduct formation was unaffected by GSH or cyclohexene oxide. 4. These results suggest that adduct formation occurred via an unknown reactive product rather than via oxazepam-epoxide, and that the relative rates of oxidative metabolism in vitro parallel that in vivo for the three species examined.
authors.affiliation: Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: L T
authors.initials: LT
authors.lastname: Burka
authors.forename: K B
authors.initials: KB
authors.lastname: Demby
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010076:Oxazepam / Q000737:chemistry / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
chemical_list: D014151:Anti-Anxiety Agents; D011506:Proteins; D010076:Oxazepam