Metabolism of chlorpromazine and promazine in vitro: Isolation and characterization of N-oxidation products

Abstract

1. The syntheses of the secondary hydroxylamines of nor₁chlorpromazine and nor₁-promazine via their corresponding primary hydroxylamines and oximes are described.

2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry.

3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and α-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits.

4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified.

5. N-hydroxynor₁- and N-hydroxynor₂chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.