Pharmacokinetic Analysis of Maprotiline and Its Demethylated Metabolite in Serum and Brain of Rats after Acute and Chronic Oral Administration of Maprotiline

Compartmental model analysis by simultaneous curve fitting was used to ascertain the pharmacokinetic relationship between maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and brain of rats after single or multiple oral administrations of MAP. The extent of bioavailability and the fraction metabolized to DMAP after acute oral administration were 0.202 and 0.065, respectively, indicating first‐pass metabolism of MAP. Although the estimated transfer rate constants to and from the brain (kin and kout) of MAP were higher than those of DMAP, the kin:kout ratio for MAP was similar to that for DMAP. These findings indicate the equivalent ability of MAP and DMAP to penetrate into the brain after acute oral administration. The estimated values of bioavailability and fraction metabolized to DMAP increased 2.6 and 1.7 times, respectively, after chronic administration of MAP. These findings are attributable to inhibited distribution in tissue. The kin and kout values of MAP decreased, whereas those of DMAP showed no marked change. Therefore, the kin:kout ratio for MAP decreased, whereas that for DMAP did not change. These results suggest that the permeability of MAP into the brain might be affected and that of DMAP is not modified by chronic administration of MAP.