Metabolic Rearrangements of 1,4-Benzodiazepine Derivatives

Abstract

1. Formation of quinazolines from 1,4-benzodiazepines represents a minor metabolic pathway.

2. In incubations of rat liver microsomal preparations with oxazepam, lorazepam, medazepam, diazepam, and chlorazepate, the quinazolin-2-ones were formed in amounts of less than 1% of added substrate without phenobarbital pre-treatment and to a maximum of 2% with phenobarbital pre-treatment.

3. 3-Hydroxy-1,4-benzodiazepines, e.g., oxazepam and 3-hydroxydiazepam, are metabolic precursors in quinazolin-2-one formation, whereas 3-oxo derivatives were excluded as metabolic intermediates.

4. 3-Methyl analogues of diazepam also yielded quinazolinones by elimination of position 3 of the diazcpine ring and additionally gave the 2-acetylquinazo-line and the 2-ethan-α-ol-quinazoline as major metabolites presumably via the same intermediate.

5. The 3-carboxylate chlordiazepate (chlorazepate) was first metabolized to oxazepam and subsequently to the quinazolin-2-one.