Promazine. A major plasma metabolite of chlorpromazine in a population of chronic schizophrenics

N-Demethylation and dehalogenation of chlorpromazine (CPZ) were compared in six psychotic inpatients and in rats orally treated for 4 weeks with a daily CPZ dose of 5.4 (mean value) and 20 mg X kg-1 body weight, respectively, by measuring drug and metabolite plasma levels by means of a gas-liquid chromatography-nitrogen/phosphorus detector method. In patients the major plasma metabolite was found to be promazine (PZ), as identified by capillary GC-MS analysis. In rats, on the contrary, PZ represented only a small proportion of the compounds detected in plasma. The mean [PZ]/[CPZ] ratio after 4 weeks of treatment was 1.64 in patients and 0.08 in rats. The relative frequency of the N-demethyl metabolites in plasma, however, was similar in the two species. The mean [N-monodemethylated CPZ]/[CPZ] and [N-didemethylated CPZ]/[CPZ] ratios after 4 weeks of treatment were 0.45 and 0.24 in patients and 0.56 and 0.25 in rats, respectively. These findings suggest that dechlorination of CPZ in psychotic patients represents an important metabolic pathway.