Distribution of clomipramine in various brain regions of rats under steady-state serum concentrations

Abstract

The clomipramine (CMP) distribution in 12 regions of rat brain was investigated 2 and 7 days after subcutaneous minipump implantation. The results of serial blood samplings during 7 days indicated that steady-state CMP serum levels were achieved from experimental day 2. The regional CMP distributions in the brains were uneven on both the 2nd and 7th experimental days. On both test days the CMP concentrations were higher in the cerebral cortex and hippocampus than those in the other regions, and those in the cerebellum and bulbus olfactorius and septum were lower. When the serial fluctuations of the CMP levels were examined in 12 brain regions, there were significant differences between days 2 and 7 in the following four regions: the anterior basal ganglia, hypothalamus, bulbus olfactorius + septum and amygdala.

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

“…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. There were uneven ATL distributions in the rat brains on the 2nd, 7th and 14th day, as shown in the previous studies of tricyclic antidepressants (TCAs) with single and/or multiple doses [7,11,16,20,25,27], The distribution pattern obtained in the present study generally resembled that of CMP [17], and was unlike the topographies of imipra mine binding sites and serotonin concentra tion in the brain [12]. There were significant differences in ATL levels between the 7th and 14th day in both ABG and PMO (ta ble 2).…”

“…It has been reported that in chronic intraperitoneal ATL administration the brain/plasma ratio for ATL reached 30 at 2 h after injection and fell to 8 at 12 h after the injection [3], It is therefore assumed that ADD brain/serum concentration ratios fluc tuate during the dosing interval and the ADD serum concentration may not reflect the steady-state brain concentration within the first week of medication, as mentioned above. Our previous study on 7-day contin uous infusion of CMP did not show any change in the CMP brain/serum concentra tion ratio [17], This may be due to some dif ference between the drugs or to the longer administration period in the present study. Glotzbach and Preskorn [14] reported that there was a linear correlation between the ATL concentrations in brain and serum in long-term ATL administration, and the brain/serum concentration ratio decreased in accordance with the increase in the ATL serum level.…”

“…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. In the previous study we examined changes in the regional brain distribution of clomipramine (CMP), a strong tricyclic serotonin uptake blocker, under long-term infusion.…”

“…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.…”

“…In the previous study we examined changes in the regional brain distribution of clomipramine (CMP), a strong tricyclic serotonin uptake blocker, under long-term infusion. It was found that CMP uptake fluctuated in several regions according to the time elapsed after the start of dosing [ 17], We also investigated whether ATL, a weaker serotonin uptake blocker than CMP. behaves similarly at a steady-state level.…”