Regional distribution of clomipramine and desmethylclomipramine in rat brain and peripheral organs on chronic clomipramine administration

The tricyclic antidepressant (TCA) clomipramine has been widely used in psychiatry for over 40 years. More recently, its therapeutic potential as an antineoplastic drug has been identified. However, there are no prior data on regional distribution in the brain of clomipramine and its primary metabolite (desmethylclomipramine) after chronic oral administration. The aim of this study was to determine the concentrations of clomipramine and desmethylclomipramine in different rat-brain regions and to compare those with levels in plasma and peripheral organs after chronic oral treatment of Sprague Dawley rats (15 mg/kg) for 14 days. The levels of both parent TCA and metabolite were analysed by high-performance liquid chromatography in six brain regions (cortex, hypothalamus, hippocampus, striatum, brainstem and cerebellum), five peripheral organs and in plasma. Our data show that the cerebral cortex had the highest concentration of clomipramine (2.9 μg/mg), with successively lower concentrations in the hypothalamus, striatum, cerebellum, hippocampus and brainstem. Of the peripheral organs, the lungs and liver, had the highest levels of clomipramine, while in the heart, only the metabolite was detected. The plasma concentration (0.17 μg/ml or 0.48 μM) was comparable to that in the hippocampus and cerebellum (approximately 0.20 μg/mg). The differential distribution of clomipramine in different brain regions and the regional variation in clomipramine to desmethylclomipramine ratios have implications for the use of clomipramine in psychiatry and neuro-oncology.