Possible involvement of cationic-drug sensitive transport systems in the brain-to-blood efflux and blood-to-brain influx of amantadine across the blood-brain barrier
Possible involvement of cationic-drug sensitive transport systems in the brain-to-blood efflux and blood-to-brain influx of amantadine across the blood-brain barrier
复制标题
阳离子药物敏感转运系统可能参与金刚烷胺穿过血脑屏障的脑到血流出和血到脑流入
DOI：
10.1002/bdd.1926
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发表时间：
2015
影响因子：
2.1
通讯作者：
Kazuo Tomono
中科院分区：
文献类型：
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作者：
Toyofumi Suzuki;Toshiro Fukami;Kazuo Tomono
本研究的目的是表征金刚烷胺穿过血脑屏障（BBB）的脑-血外排转运。采用脑外排指数法，发现脑内微量注射后[3 H]金刚烷胺的表观体内外排速率常数（keff）为1.53 × 10 - 2 min-1。[3 H]金刚烷胺的外排被1-甲基-4-苯基吡啶鎓（MPP+）（一种阳离子神经毒素）抑制，表明金刚烷胺从脑到血液的跨血脑屏障转运可能涉及大鼠质膜单胺转运蛋白（rPMAT）。另一方面，有机阳离子转运蛋白（OCT）和有机阴离子转运蛋白（OAT）的其他选定底物以及P-糖蛋白（P-gp）抑制剂不影响[3 H]金刚烷胺的外排转运。此外，使用永生化大鼠脑内皮细胞系（GPNT）的体外研究表明，加入环孢菌素（一种P‐gp抑制剂）不会改变细胞对[3 H]金刚烷胺的摄取和保留。然而，环孢菌素影响罗丹明123的吸收和保留。最后，采用原位脑灌注技术测定[3 H]金刚烷胺的初始脑摄取。值得注意的是，[3 H]金刚烷胺的脑摄取清除率随着奎尼丁或维拉帕米（阳离子P-gp抑制剂）的共同灌注而显著降低，而MPP+没有显著影响。因此得出结论，虽然不涉及P-gp，但rPMAT和阳离子药物敏感转运系统可能分别参与金刚烷胺穿过BBB的脑-血流出和血-脑流入。版权所有© 2014约翰威利父子有限公司.
The purpose of this study was to characterize the brain‐to‐blood efflux transport of amantadine across the blood–brain barrier (BBB). The apparentin vivoefflux rate constant for [3H]amantadine from the rat brain (keff) was found to be 1.53 × 10‐2min‐1after intracerebral microinjection using the brain efflux index method. The efflux of [3H]amantadine was inhibited by 1‐methyl‐4‐phenylpyridinium (MPP+), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB potentially involves the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P‐glycoprotein (P‐gp), did not affect the efflux transport of [3H]amantadine. In addition,in vitrostudies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [3H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P‐gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [3H]amantadine was determined using anin situmouse brain perfusion technique. Notably, the brain uptake clearance for [3H]amantadine was significantly decreased with the co‐perfusion of quinidine or verapamil, which are cationic P‐gp inhibitors, while MPP+did not have a significant effect. It is thus concluded that while P‐gp is not involved, it is possible that rPMAT and the cationic drug‐sensitive transport system participate in the brain‐to‐blood efflux and the blood‐to‐brain influx of amantadine across the BBB, respectively. Copyright © 2014 John Wiley & Sons, Ltd.