A COMPREHENSIVE INVESTIGATION OF PLASMA AND BRAIN REGIONAL PHARMACOKINETICS OF IMIPRAMINE AND ITS METABOLITES DURING AND AFTER CHRONIC ADMINISTRATION IN THE RAT

The relationship between the serum imipramine concentration and its an tidepressant effects remain undefined despite >30 years of clinical in vestigation. No study to date has assessed the kinetic relationships b etween the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmac okinetics of imipramine (IMI) and its desmethylated and hydroxylated m etabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal f luid, and six brain structures were measured by high-performance liqui d chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and dides methylimipramine (DDMI) in brain tissue were much higher than in the s erum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination half -lives of desmethylated compounds increased with the degree of desmeth ylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into ac count in clinical investigations of the effects of serum concentration s of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebra l tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clea rly established. Finally, there were significant differences in the di stributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in hu mans.