Adverse Effects of Chlorpromazine Metabolites on Isolated Hepatocytes

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Abstract
Chlorpromazine (CPZ) and several of its metabolites were tested for in vitro cytotoxicity, as measured by efflux of aspartate aminotransferase to the surrounding medium, toward isolated rat hepatocytes. Exposure of liver cells to CPZ, at a concentration of 9 .times. 10-5 M, led to enzyme leakage. The demethylated metabolites, mono- and didesmethyl-CPZ, were 3 and 6 times, respectively, more potent than CPZ. Hydroxylation of the tricyclic ring at the 7 or 8 position gives rise to compounds that were slightly less active than the parent compound, while oxidation of the S atom resulted in inactive analogs. The presence of Ca in the medium had no apparent effect on the response of the hepatocytes to CPZ.