Sakata A, Tamai I, Kawazu K, Deguchi Y, Ohnishi T, Saheki A, Tsuji A
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Biochem Pharmacol. 1994 Nov 16;48(10):1989-92. doi: 10.1016/0006-2952(94)90601-7.
To evaluate the significance of P-glycoprotein (P-gp)-mediated active efflux on the blood-brain barrier (BBB) permeability of cyclosporin A (CsA) in vivo, we investigated the effects of ATP depletion in the brain and of a multidrug-resistant (MDR) reversing agent on the transport of CsA across the BBB. Using transient brain ischemia obtained by 4-vessel occlusion of vertebral and common carotid arteries in rats to deplete ATP content in the brain, the estimated permeability surface area product (PS) value of [3H]CsA was increased 2.7-fold compared with that in normal rats, whereas the PS value of [14C]sucrose was not altered. Additionally, when quinidine hydrochloride (QND) was infused into the brain through a microdialysis probe implanted in the rat hippocampus, the extravascular extraction of CsA was increased to approximately 2.5-fold of the control, whereas no difference in the extravascular extraction between control and normal rats having no implanted dialysis probe was observed. Furthermore, the efflux rate from brain to blood of CsA was decreased remarkably to 5% of control at steady-state by co-administration of CsA with QND directly into the brain through the dialysis probe. The ATP-dependent and QND-sensitive efflux of CsA from the brain strongly indicates that P-gp in the brain capillary endothelial cells functions as an efflux pump under the physiological state, and that P-gp-mediated efflux of CsA is a major mechanism of the restricted transfer from blood into the brain.
为了评估P-糖蛋白（P-gp）介导的主动外排在体内对环孢素A（CsA）血脑屏障（BBB）通透性的影响，我们研究了脑内ATP耗竭和一种多药耐药（MDR）逆转剂对CsA跨BBB转运的影响。通过对大鼠椎动脉和颈总动脉进行四血管闭塞诱导短暂性脑缺血以耗尽脑内ATP含量，[3H]CsA的估计通透表面积乘积（PS）值相较于正常大鼠增加了2.7倍，而[14C]蔗糖的PS值未改变。此外，当通过植入大鼠海马体的微透析探针向脑内注入盐酸奎尼丁（QND）时，CsA的血管外提取率增加至对照的约2.5倍，而在对照大鼠和未植入透析探针的正常大鼠之间未观察到血管外提取率的差异。此外，通过透析探针将CsA与QND直接共同注入脑内，在稳态时CsA从脑到血的外排率显著降低至对照的5%。CsA从脑内的ATP依赖性和QND敏感性外排强烈表明，脑毛细血管内皮细胞中的P-gp在生理状态下起外排泵的作用，并且P-gp介导的CsA外排是限制CsA从血液进入脑内的主要机制。
