Weber C C, Kressmann S, Ott M, Fricker G, Müller W E
Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, Germany.
Pharmacopsychiatry. 2005 Nov;38(6):293-300. doi: 10.1055/s-2005-916184.
In many depressive patients the negative feedback mechanism of the HPA (hypothalamic-pituitary-adrenocortical) axis is impaired. It has been suggested that antidepressants inhibit membrane glucocorticoid transporters like P-Glycoprotein (Pgp) and hence enhance the intracellular glucocorticoid concentration, leading to an increased glucocorticoid-receptor mediated gene transcription and therefore to normalization of the function of the HPA axis. The aim of this study is to investigate inhibition of Pgp by several different antidepressants.
We characterized the inhibitory potencies of the antidepressants in two in vitro assays by using calcein-AM as Pgp substrate. The two different cell-systems expressing Pgp were: 1. PBCEC (porcine brain capillary endothelial cells) as model for the blood-brain-barrier, and 2. A human lymphocytic leukaemia cell line CEM and the multi-drug-resistant (MDR) cell line VLB-100, expressing Pgp as model for the human protein.
All of the antidepressants tested inhibit the transport of calcein-AM by Pgp in the micromolecular range.
Because this inhibition is only seen at concentrations above therapeutically relevant plasma levels, their effect my not play a role for the mechanism of action of the antidepressants tested.
在许多抑郁症患者中，下丘脑-垂体-肾上腺皮质（HPA）轴的负反馈机制受损。有人提出，抗抑郁药会抑制诸如P-糖蛋白（Pgp）之类的膜糖皮质激素转运蛋白，从而提高细胞内糖皮质激素浓度，导致糖皮质激素受体介导的基因转录增加，进而使HPA轴功能恢复正常。本研究的目的是研究几种不同抗抑郁药对Pgp的抑制作用。
我们通过使用钙黄绿素-AM作为Pgp底物，在两种体外试验中对这些抗抑郁药的抑制效力进行了表征。两种表达Pgp的不同细胞系分别为：1. 猪脑毛细血管内皮细胞（PBCEC）作为血脑屏障模型；2. 人淋巴细胞白血病细胞系CEM和表达Pgp的多药耐药（MDR）细胞系VLB-100作为人类蛋白质模型。
所有测试的抗抑郁药在微分子范围内均抑制Pgp介导的钙黄绿素-AM转运。
由于这种抑制作用仅在高于治疗相关血浆水平的浓度下才会出现，因此它们的作用可能对所测试抗抑郁药的作用机制不起作用。
