The pharmacokinetic profiles of clomipramine (CMP) and the serial changes of its concentration in specific brain regions were investigated in rats after an acute treatment with intravenous CMP (10 mg/kg). The CMP concentrations in plasma declined triexponentially and fitted a three‐compartment open model. The brain to plasma concentration ratio showed a constant value, 22.2 ± 4.9, 30 minutes after the injection. Regional brain differences in the CMP distribution and accumulation were also found. Four hours after the injections, the hippocampus was found to have the highest drug concentration, and the concentrations in this region were in the following order; thalamus, striatum, amygdala, cortex > pons + medulla oblongata > hypothalamus, bulbus olfactorius + septum, mesencephalon > cerebellum. Particularly, unique kinetics were observed in the cortex, amygdala and hippocampus.
The relationship between clomipramine (CMP) brain concentration and its inhibitory effect on serotonin (SHT) turnover was investigated in rats treated with a single dose and multiple doses of CMP. CMP reduced the 5-hydroxyindole acetic acid (SHIAA) brain levels in two groups of rats. Concerning the S H T turnover measured by the probenecid (PBC) technique, there were significant correlations between the CMP brain level (x) and SHIAA brain level (y) after PBC injections in both acute and chronic experiments. The regression lines for the respective groups were y = 764 -1171og x (r = 0.84, P < 0.001) and y -770 -97.7 log x (r -0.68, P < 0.001). The regression coefficient for the acute experiment was greater than that for the chronic one (p < 0.001), indicating a less dose-response in the latter. From these findings, the acute dosing with CMP seemed to reduce the SHT turnover without reference to the dose but a prolonged administration seemed to vary in its effect. This may be due to a compensatory mechanism in the SHT system induced by chronic CMP-treatment.
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