THE METABOLISM OF CHLORPROMAZINE BY LIVER MICROSOMAL ENZYME SYSTEMS

¹ Department of Biochemistry, State University of New York, Upstate Medical Center, Syracuse, New York

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.

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