Inhibition of P-glycoprotein:: Rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier
Inhibition of P-glycoprotein:: Rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier
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DOI：
10.1023/a:1011913723928
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发表时间：
1998-07-01
影响因子：
3.7
通讯作者：
Dehouck, MP
中科院分区：
文献类型：
--
作者：
Fenart, L;Buée-Scherrer, V;Dehouck, MP
目的：本研究的目的是在体外评估p -糖蛋白依赖药物在与逆转剂联合使用时通过脑毛细血管内皮细胞的能力。采用脑毛细血管内皮细胞和星形胶质细胞共培养的体外血脑屏障模型。我们证明星形胶质细胞的存在上调了p糖蛋白的表达。研究了长春新碱、环孢素A和阿霉素在细胞内的摄取和内皮细胞单层间的转运。使用S9788或维拉帕米作为逆转剂，我们发现长春新碱通过内皮细胞单层的转运增加。另一方面，S9788或维拉帕米与环孢素A的关联并没有增加该药物的转运。由于内皮细胞单层破裂，阿霉素从腔室到腔室的转运也增加。使用该模型，可以预测p -糖蛋白依赖药物通过大脑或在脑毛细血管内皮细胞中的隔离，当该药物与逆转剂相关时，或其对血脑屏障完整性的毒性。
Purpose, The objective of this work was to assess, in vitro, the passage of P-glycoprotein dependent drugs across brain capillary endothelial cells, when these drugs are associated with a reversing agent.Methods. An in vitro model of the blood-brain barrier consisting of a coculture of brain capillary endothelial cells and astrocytes was used.Results. We demonstrate that P-glycoprotein expression is upregulated by the presence of astrocytes. Uptake in the cells and transport across endothelial cell monolayers of vincristine, cyclosporin A and doxorubicin were studied. Using S9788 or verapamil as reversing agents, we found an increase in vincristine transport across the endothelial cell monolayers. On the other hand, the association of S9788 or verapamil with cyclosporin A failed to increase the transport of this drug. An increase in the transport of doxorubicin from luminal to abluminal compartment was also observed, due to endothelial cell monolayer breakdown.Conclusions. Using this model, it is possible to predict the passage of a P-glycoprotein dependent drug to the brain or its sequestration in brain capillary endothelial cells when this drug is associated with a reversing agent, or its toxicity on the blood-brain barrier integrity.