Uhr Manfred, Grauer Markus T, Holsboer Florian
Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany.
Biol Psychiatry. 2003 Oct 15;54(8):840-6. doi: 10.1016/s0006-3223(03)00074-x.
Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain.
One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured.
The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups.
The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.
利用多重耐药（abcb1ab）基因发生遗传破坏（敲除）的小鼠，研究血脑屏障处缺乏药物转运蛋白P-糖蛋白（P-gp）对抗抑郁药文拉法辛、帕罗西汀、米氮平和多塞平及其代谢产物进入脑内的影响。
皮下注射文拉法辛、帕罗西汀、米氮平或多塞平1小时后，处死敲除小鼠和野生型小鼠，测量脑、脾、肾、肝和血浆中的药物浓度。
敲除小鼠脑中多塞平、文拉法辛和帕罗西汀的浓度较高，表明这些物质是P-gp的底物，且血脑屏障处的abcb1ab活性会降低这些物质进入脑内的渗透率。相比之下，两组小鼠脑中米氮平的分布无差异。
此处报道的抗抑郁药脑渗透率因abcb1ab基因的存在与否而产生的差异，可能为抗抑郁治疗效果不佳或无反应提供一种解释。此外，它们可能部分解释抗抑郁药血浆水平与其临床疗效和副作用之间的差异。
