Uptake and efflux of quinacrine, a candidate for the treatment of prion diseases, at the blood-brain barrier
Uptake and efflux of quinacrine, a candidate for the treatment of prion diseases, at the blood-brain barrier
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DOI：
10.1023/b:cemn.0000018617.21378.95
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发表时间：
2004-04-01
影响因子：
4
通讯作者：
Kataoka, Y
中科院分区：
文献类型：
--
作者：
Dohgu, S;Yamauchi, A;Kataoka, Y
1. 一项针对克雅氏病的临床试验正在进行中。药物通过血脑屏障（BBB）的通透性是其治疗朊病毒疾病疗效的决定因素。用小鼠脑内皮细胞（MBEC4）研究了醌类药物通过血脑屏障的转运机制。喹啉通过MBEC4细胞的通透性低于荧光素钠（一种不透血脑屏障的标记物）。quinacrine基底外侧到根尖的转运大于根尖到基底外侧的转运。在p -糖蛋白（P-gp）抑制剂、环孢素或维拉帕米存在的情况下，醌的根尖向基底侧转运增加。在环孢素或维拉帕米的存在下，MBEC4细胞对阿奎宁的摄取增强。Quinacrine的摄取是高度集中的，这一事件是由饱和和载体介导的系统进行的，表观K-m为52.1 muM。醌的摄取对Na+耗竭和膜电位的变化不敏感，对ph的变化敏感。四乙基铵和西咪替丁（有机阳离子转运体的底物和抑制剂）分别降低了醌的摄取。这些发现表明，阿奎宁在血脑屏障的转运是由外排系统（P-gp）和内流系统（有机阳离子转运体样机械）介导的。
1. A clinical trial of quinacrine in patients with Creutzfeldt - Jakob disease is now in progress. The permeability of drugs through the blood - brain barrier (BBB) is a determinant of their therapeutic efficacy for prion diseases. The mechanism of quinacrine transport across the BBB was investigated using mouse brain endothelial cells (MBEC4).2. The permeability of quinacrine through MBEC4 cells was lower than that of sodium fluorescein, a BBB-impermeable marker. The basolateral-to-apical transport of quinacrine was greater than its apical-to-basolateral transport. In the presence of P-glycoprotein (P-gp) inhibitor, cyclosporine or verapamil, the apical-to-basolateral transport of quinacrine increased. The uptake of quinacrine by MBEC4 cells was enhanced in the presence of cyclosporine or verapamil.3. Quinacrine uptake was highly concentrative, this event being carried out by a saturable and carrier-mediated system with an apparent K-m of 52.1 muM. Quinacrine uptake was insensitive to Na+-depletion and changes in the membrane potential and sensitive to changes in pH. This uptake was decreased by tetraethylammonium and cimetidine, a substrate and an inhibitor of organic cation transporters, respectively.4. These findings suggest that quinacrine transport at the BBB is mediated by the efflux system (P-gp) and the influx system ( organic cation transporter-like machinery).