Brain distribution of ribavirin after intranasal administration
Brain distribution of ribavirin after intranasal administration
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DOI：
10.1016/j.antiviral.2011.09.012
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发表时间：
2011-12-01
影响因子：
7.6
通讯作者：
Scagliarini, Alessandra
中科院分区：
文献类型：
--
作者：
Colombo, Gaia;Lorenzini, Luca;Scagliarini, Alessandra
利巴韦林已被证明在体外对几种引起人类和动物脑炎的RNA病毒有效。然而，对脑病毒载量的体内疗效似乎受到血脑屏障的限制。由于鼻-脑通路被认为是药物输送到大脑的途径，我们在此研究了利巴韦林鼻腔给药后在中枢神经系统(CNS)的分布。我们首先利用Franz细胞和兔鼻粘膜，测试了利巴韦林从水溶液中跨越生物膜的体外扩散。约35%的利巴韦林在4h内通过黏膜，在不到30min的时间内达到稳态渗透。在第一次体内实验中，给SD大鼠鼻腔注射利巴韦林水溶液(10 mg/kg)。分别于给药后10、20、30min处死动物，收集脑区(小脑、嗅球、大脑皮层、基底节和海马区)和生物液(脑脊液和血浆)。LC-MS/MS法定量检测各时间点的利巴韦林，嗅球浓度最高，吻尾方向浓度最小。随后的两个体内实验比较了鼻腔给药(利巴韦林溶液)与静脉给药以及利巴韦林溶液与利巴韦林粉剂(10 mg/kg)鼻腔给药的效果。结果发现，给药后20min，静脉和鼻腔给药后，利巴韦林在嗅球中的浓度基本相同，而粉剂的浓度则显著升高。利巴韦林也存在于更深的脑室，如基底节和海马区。即使参与利巴韦林鼻到脑转运的机制尚不清楚，这些结果表明，利巴韦林从鼻上皮到嗅球和不同的中枢神经系统区域有快速的细胞外扩散流。(C)2011爱思唯尔B.V.保留所有权利。
Ribavirin has proved to be effective in vitro against several RNA viruses responsible for encephalitis in humans and animals. However, the in vivo efficacy towards the cerebral viral load seems to be limited by the blood-brain barrier. Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we investigated here the distribution of ribavirin in the central nervous system (CNS) after intranasal administration. We first tested in vitro ribavirin diffusion from an aqueous solution across a biological membrane, using Franz cells and rabbit nasal mucosa. About 35% of ribavirin permeated in 4 h across the mucosa, after reaching steady-state flux in less than 30 min. In the first in vivo experiment, ribavirin aqueous solution was administered intranasally to Sprague Dawley rats (10 mg/kg). Animals were sacrificed at 10,20 or 30 min after administration to collect brain areas (cerebellum, olfactory bulb, cerebral cortex, basal ganglia and hippocampus) and biological fluids (cerebrospinal fluid and plasma). Ribavirin, quantified by LC-MS/MS spectrometry, was detected at each time point in all compartments with the highest concentration in olfactory bulb and decreasing in rostro-caudal direction. Two subsequent in vivo experiments compared the nasal route (ribavirin solution) with the intravenous one and the nasal administration of ribavirin solution with ribavirin powder (10 mg/kg). It was found that 20 min after administration, ribavirin concentration in olfactory bulb was similar after intravenous or nasal administration of the ribavirin solution, whereas the powder led to significantly higher levels. Ribavirin was also present in deeper compartments, such as basal ganglia and hippocampus.Even if the mechanisms involved in ribavirin nose-to-brain transport are not clear, these results suggest a rapid extracellular diffusive flux from the nasal epithelium to the olfactory bulb and different CNS areas. (C) 2011 Elsevier B.V. All rights reserved.