Pharmacokinetics of chlorimipramine and its demethylated metabolite in blood and brain regions of rats treated acutely and chronically with chlorimipramine.

The pharmacokinetic profiles for chlorimipramine (CIM) and its demethylated metabolite desmethylchlorimipramine (DCIM) in blood and in specific brain regions were obtained in rats after acute or chronic treatment with 15 mg/kg of the tricyclic antidepressant CIM. In blood, chronic drug treatment resulted in 1) a decrease in the time to maximal concentration of DCIM; 2) increases in maximal concentrations of CIM and of DCIM; and 3) a decrease in T1/2 of elimination of both CIM and DCIM. These changes induced a small reduction in the area under the CIM curve and a 4-fold increase in the area under the DCIM curve. In brain, both CIM and DCIM were unevenly distributed after both treatment schedules. Maximal accumulations of CIM and DCIM elimination were greatly enhanced in all brain areas by the chronic treatment. In brain, the area under the CIM concentration-time curve was only slightly affected by the chronic treatment, chronic drug treatment induced a 4-fold increase in the DCIM area. The subcellular distribution of CIM and DCIM in brain was similar in the acutely and chronically treated animals. The highest specific activity was found in the soluble fraction. These results demonstrate 1) regional brain differences in CIM and DCIM distribution and accumulation; 2) differences in pharmacokinetics between acute and chronic tricyclic antidepressant drug treatment regimens; and 3) differences between blood and brain drug and metabolite pharmacokinetics were observed which suggest that generalizations based on blood parameters should be made with great caution.