Oxidative biotransformation of oxazepam to reactive and nonreactive products in rat, mouse and human microsomes.
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.
Griffin
R J
RJ
Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Burka
L T
LT
Demby
K B
KB
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
D014151:Anti-Anxiety Agents; D011506:Proteins; D010076:Oxazepam