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Pharmacokinetics of Chlorimipramine, Chlorpromazine and their N‐Dealkylated Metabolites in Plasma of Healthy Volunteers After a Single Oral Dose of the Parent Compounds

Abstract— A single oral dose of 0·7 mg kg−1 clorimipramine (n= 18) and chlorpromazine (n= 16) was given to each subject 45 days apart and plasma concentrations of parent drugs and their monodesmethyl and didesmethyl metabolites were measured by GC. Ingestion of chlorimipramine resulted in an area under the plasma concentration‐time curve (AUC 0–24) for parent drug plus metabolites 5‐fold higher than that observed in the same subjects following chlorpromazine intake (600 ± 87 and 124 ± 14 ng mL−1, respectively). Plasma chlorimipramine levels reached a mean peak value of 43·8 ng mL−1, an average of 3·4 h after dosage, whereas the mean peak chlorpromazine level was 15·1 ng mL−1, which occurred 2 h after administration. Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination rate‐limited and those of chlorpromazine appeared to be formation‐rate‐limited. The response to single doses of these two drugs in healthy subjects highlights the two distinct dispositional processes involved, thus offering pharmacokinetic explanation of the hitherto empirical discrepancy in dosage levels in chronic treatment.