Rat Tissue Concentrations of Chlorimipramine, Chlorpromazine and their N-Demethylated Metabolites after a Single Oral Dose of the Parent Compounds

Abstract

Abstract A single oral dose of 90 mg kg−1 chlorimipramine or chlorpromazine, corresponding to 54.5 or 55.9 μmol, respectively, was given to male Sprague-Dawley rats and concentrations of parent drugs and their N-desmethyl metabolites measured by gas chromatography in plasma and major organs (brain, liver, lung, kidney, heart, spleen and peritoneal fat). In the case of chlorimipramine, N-desmethyl metabolite levels were consistently higher than those of the parent drug for the entire observation period of 24 h in all tissues except fat, while lower N-desmethyl metabolite/parent compound ratios were observed for chlorpromazine. N-Desmethyl metabolite kinetics of chlorimipramine appeared to be elimination-rate limited, while those of chlorpromazine were formation-rate limited. In all analysed organs, the maximum detectable drug + metabolite concentrations accounted for only 2·3 and 4·6% of the initial dose of chlorimipramine and chlorpromazine. Chlorpromazine treatment gave rise to an area under the total amount-time curve (AUC0–24) for parent drug + metabolites, 3·9-fold that for chlorimipramine. Closer scrutiny discloses a conversion ratio of parent compound to N-desmethyl metabolite of 1·1 for chlorpromazine and of 2·2 for chlorimipramine, indicating the greater efficiency of chlorimipramine metabolism in all compartments. The expected high conversion index found in the liver (2·3) reaches its maximum of 5·4 in the lung. Fractional data analysis of chlorimipramine and chlorpromazine distribution patterns revealed greater organ transfer for the N-desmethyl metabolites than for the more stably-located parent compounds. The N-desmethyl metabolites of chlorimipramine apparently moved from liver to lung, kidney and spleen, whereas N-desmethylchlor-promazine moved preferentially to the brain and lung tissue. This single dose study of chlorimipramine and chlorpromazine kinetics, highlights the two distinct dispositional processes at work in the rat in all likelihood, attributable to different absorption patterns, to a slower metabolism and, thus, to the longer persistence of chlorpromazine.