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'-hydroxyox azepam and oxazepam-dihydrodiol in NADPH-containing incubations.

2 Covalent protein adducts were increased by the addi tion 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 incuba tions. Two additional metabolites were produced under these conditions. One of these was tentatively identified as a GSH conjugate. Covalent adduct formation was unaffect ed 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.

Keywords

oxazepam microsomes biotransformation adducts dihydrodiol

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