Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats
Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats
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DOI：
10.1016/j.brainresbull.2020.04.012
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发表时间：
2020-07-01
影响因子：
3.8
通讯作者：
Erdo, Franciska
中科院分区：
文献类型：
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作者：
Bors, Luca Anna;Bajza, Agnes;Erdo, Franciska
在过去的几十年中，开发了几种新的药物制剂以从鼻腔靶向中枢神经系统（CNS）。然而，在这些研究中，较少关注在多药治疗的情况下可能的药物相互作用。在我们的初步研究中，我们首先比较了鼻溶液和鼻凝胶，以证明它们在鼻腔中的分布（3D打印大鼠头骨模型和组织学）。由于吸入诱导鼻用溶液给药时的高死亡率，仅使用奎尼丁凝胶制剂继续研究。我们实验的目的是确定P-糖蛋白（P-gp）在鼻腔药物吸收中可能的功能作用，并测试鼻-脑递送时的药物间相互作用。因此，在静脉（IV）给予PSC-833（特异性P-gp抑制剂）或以低（50 ng）或高（20 μ g）剂量IN和肾上腺素（IN）的情况下，通过鼻内（IN）给药检测P-gp底物模型药物奎尼丁。在对照动物中，奎尼丁的脑渗透处于检测限水平，但在与IV PSC-833联合治疗中，脑水平急剧增加，与高剂量IN肾上腺素类似，由于血管收缩，外周分布被阻断。这些结果表明，P-gp在鼻腔的药物吸收和流出中具有重要作用，而肾上腺素也能够改变P-gp底物模型药物在鼻腔应用中的渗透特性，因为它降低了鼻-血吸收，使更多的奎尼丁沿着鼻神经到达大脑。
During the last decades several new drug formulations were developed to target the central nervous system (CNS) from the nasal cavity. However, in these studies less attention was paid to the possible drug-drug interactions in case of multi-drug therapy. In our pilot study first we compared a nasal solution and a nasal gel to demonstrate their distribution in the nasal cavity (3D printed rat skull model and histology). Due to the aspiration induced high mortality at administration of nasal solution the study was continued only with the gel formulation of quinidine. The aim of our experiments was to identify the possible functional role of P-glycoprotein (P-gp) in the drug absorption in nasal cavity and to test drug-drug interactions at nose-to-brain delivery. Therefore, a P-gp substrate model drug, quinidine was tested by intranasal (IN) administration in presence of PSC-833 (specific P-gp inhibitor) given intravenously (IV) or IN and adrenaline (IN) at low (50 ng) or high (20 mu g) dose. In control animals the brain penetration of quinidine was at the level of detection limit, but in combination therapy with IV PSC-833 the brain levels increased dramatically, similarly to high dose IN adrenalin, where due to vasoconstriction peripheral distribution was blocked. These results indicate that P-gp has an important role in drug absorption and efflux at nasal cavity, while adrenaline is also able to modify the penetration profile of the P-gp substrate model drug at nasal application as it decreases nose-to-blood absorption, letting more quinidine to reach the brain along with the nasal nerves.