A Pharmacokinetic Study of Clomipramine in Regions of the Brain

Abstract

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.

Changes in Amitriptyline Distribution in Rat Brain during a 14-Day Continuous Infusion

“…In the present study, NTL concentrations in rat brain and serum were much lower than those of ATL, in contrast to findings in human plasma [4,5], This difference in drug metabolism between rats and humans is also seen in déméthylation catabolism of CMP [16]. This result, low NTL/ATL ratios in the brain and serum, may be due to differences not only in species but also in the route of the administration.…”

“…However, this relation was not found within the ATL concentration range of the present study. The minipump method is suitable for the study of regional drug distribution in the brain, since fluctuations in drug serum level can be minimized [16,17,22], The data from each region were analyzed using 3 pa rameters, absolute ATL concentration, T/W ratio and B/S ratio. As shown in table 2, the T/W ratio was the most appropriate for the present study, because only a study of the T/W ratio could clearly demonstrate both the uneven ATL distribution in the brain and the time X region interaction.…”

“…ATL and NTL concentrations in brains and serum were measured by high-performance liquid chromatogra phy using CMP as an internal standard according to the previous report, with slight modification [16]. The instrument was fitted with a 25 cm X 4.6 mm (i.d.)…”

“…On the 2nd, 7th and 14th day after the operations, the animals, whose weights were 250-300 g, 310-355 g and 320-375 g. respectively, were decapitated, the brains removed and blood samples were taken. The brains were dis sected immediately on ice into the following regions [16]: bulbus olfactorius + septum (BOS), anterior basal ganglia (ABG), posterior basal ganglia (PBG), frontal cortex (FC). occipital cortex (OC).…”

“…Several studies of ADD uptake in brain have indicated uneven distribution in experimental animals given single and/or multiple dosings [7,11,16,20,25,27]. However, it seems that the designs of these studies, which imply intravenous or intraperitoneal administration, are not ade quate for comparison with the situation in humans, in whom steady-state serum levels of ADDs are attained [22], To our knowl edge there has been only our report concern ing the heterogeneous ADD distribution in brain under the chronic steady-state condi tion [17], This method is suitable for investi gating detailed serial changes in the regional distribution of ADD in the brain under chronic administration, as fluctuations in ADD serum concentrations can be mini mized during long-term experiments.…”