PHARMACOKINETICS OF MAPROTILINE AND ITS DEMETHYLATED METABOLITE IN SERUM AND SPECIFIC BRAIN-REGIONS OF RATS AFTER ACUTE AND CHRONIC ADMINISTRATION OF MAPROTILINE

The concentrations of maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of MAP in rats. MAP was eliminated in a biexponential manner from the serum and monoexponentially from the brain. The DMAP declined monoexponentially from the serum and brain regions. No significant difference was observed in elimination among the eight brain regions examined. In the brain, MAP distributed unevenly after chronic administration, whereas DMAP showed an even distribution. In the acute administration, the AUC(brain):AUC(serum) ratio of MAP was similar to that of DMAP, and the AUC(DMAP):AUC(MAP) ratio in the serum was almost equal to that in the brain, indicating equivalent ability of MAP and DMAP to penetrate into the brain. After chronic administration, the AUC(DMAP) value in the serum increased 4.1 times, whereas no marked change was observed for MAP. There was no evidence of enhanced N-demethylation activity from in vitro metabolism study, suggesting that the enhanced AUC(DMAP) value was not attributable to the enhancement of drug metabolizing activity. Although the AUC(MAP) value in the brain, as well as in the serum, increased slightly, the AUC(DMAP) in the brain increased 2.3 times, showing less increase than that in the serum. These findings suggest inhibited distribution of DMAP into tissue, including brain regions, after chronic administration. The pharmacokinetics of the demethylated metabolite DMAP is affected more than that of MAP by chronic administration of MAP.