Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood-brain barrier
Differential in vivo sensitivity to inhibition of P-glycoprotein located in lymphocytes, testes, and the blood-brain barrier
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DOI：
10.1124/jpet.105.099648
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Wilkinson, Grant R.
中科院分区：
文献类型：
--
作者：
Choo, Edna F.;Kurnik, Daniel;Wilkinson, Grant R.
血脑屏障的主要功能成分是P-糖蛋白。原则上，抑制这种外流转运体将允许其底物更多地分布到大脑中，并增加中枢效应。使用阿片类药物洛哌丁胺作为小鼠体内的探针，研究了有效和选择性的P-糖蛋白抑制剂他奎达尔和伊拉喀达。这两种抑制剂的预处理将静脉注射的洛哌丁胺从没有中枢作用的药物转变为产生抗伤害作用的药物。放射性标记的洛哌丁胺组织分布研究表明，在血浆水平没有变化的情况下，抑制作用与脑和睾丸摄取增加有关，同时CD3e(+)T淋巴细胞罗丹明123的外流增加。然而，与罗丹明123排泄曲线(ED50=0.25 mg/kg)相比，服用他奎达后，洛哌丁胺在睾丸/血浆和脑/血浆浓度比的量效曲线分别右移了6倍(p=0.07)和25倍(p=0.01)(ED50=1.48和5.65 mg/kg)。Elacridar的变化不那么明显，其脑/血浆比相对于罗丹明123的流出数据仅移动了2倍(ED50分别为2.36和1.34 mg/kg；p<；0.01)。这些结果表明，P-糖蛋白定位于血脑屏障，在较小程度上，睾丸血屏障比其他组织部位(如淋巴细胞)更耐受抑制；而且，这种影响的程度取决于抑制物。这种耐药性可以通过足够高剂量的抑制剂来克服；然而，在临床情况下是否可以安全地实现这一点仍有待确定。
A major functional component of the blood-brain barrier is P-glycoprotein. In principle, inhibition of this efflux transporter would permit greater distribution of its substrates into the brain and increased central effects. Tariquidar and elacridar, potent and selective P-glycoprotein inhibitors, were investigated in this regard using the opioid loperamide as an in vivo probe in mice. Pretreatment with both inhibitors converted intravenous loperamide from a drug without central effects to one producing antinociception. Radiolabeled loperamide tissue distribution studies indicated that inhibition was associated with increased uptake into brain and testes in the absence of changes in plasma levels, along with enhanced efflux of rhodamine 123 from CD3e(+) T-lymphocytes. However, with tariquidar, the loperamide dose-response curves for testes/plasma and brain/plasma concentration ratios were shifted 6- ( p = 0.07) and 25-fold (p = 0.01) to the right, respectively (ED50 = 1.48 and 5.65 mg/kg), compared with the rhodamine 123 efflux curve (ED50 = 0.25 mg/kg). Less pronounced shifts were noted with elacridar where the brain/plasma ratio was shifted only 2-fold relative to the rhodamine 123 efflux data (ED50 = 2.36 versus 1.34 mg/kg, respectively; p < 0.01). These results indicate that the P-glycoprotein localized in the blood-brain barrier and, to a lesser extent, the testes-blood barrier is more resistant to inhibition than at other tissue sites such as the lymphocyte; moreover, the extent of this effect depends on the inhibitor. Such resistance can be overcome by a sufficiently high dose of an inhibitor; however, whether this is safely attainable in the clinical situation remains to be determined.