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.
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