Abstract

The metabolic pathways by which chlorpromazine and its metabolites are transformed in vitro by rat and human liver microsomal enzyme systems were studied in detail. By use of a new method for isolating metabolites from incubation mixtures, thin-layer chromatography and radiochemical quantification, the following pathways have been demonstrated: demethylation of tertiary and secondary amine metabolites, oxidative deamination of primary amines, N-oxidation of tertiary amines, N-oxide reduction, sulfoxidation and aromatic ring hydroxylation of nonsulfoxidized metabohites at position 7 and to a lesser extent at position 3. SKF-525A inhibited all transformations except N-oxidation and N-oxide reduction. A nonenzymatic, ferrous iron-catalyzed oxidation of chlorpromazine gave ring hydroxylation at positions 7 and 3, sulfoxidation and traces of monodemethylation. Ferrous iron also catalyzed the rearrangement of the N-oxide to desmonomethyl chlorpromazine and to chlorpromazine sulfoxide, as well as the reduction of the N-oxide to chlorpromazine.