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Changes of serotonin and catecholamines are related to pharmacokinetic alterations of clomipramine in rat brain.

When rats received a single i.p. injection of clomipramine (20 mg/kg), clomipramine and desmethylclomipramine were rapidly distributed into the brain and their concentrations were markedly higher in the brain than in the serum, while the concentration of the metabolite in the brain was much lower than that of clomipramine. Chronic administration of clomipramine gradually increased the concentrations of the metabolite in both serum and brain, but did not significantly change those of clomipramine. The levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites in the brain were compared with the concentrations of clomipramine and desmethylclomipramine at different times. The levels of 5-HT, NE, DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain did not appear to be affected by changes in the concentrations of the drug and metabolite. The level of 5-hydroxyindole acetic acid (5-HIAA) was reduced following clomipramine injection and the reduced level was maintained during chronic treatment. Chronic treatment for more than 7 days increased the 3-methoxy-4-hydroxyphenylglycol (MHPG) level with no alteration of NE level. This elevation appeared to be induced by desmethylclomipramine.