Intranasal Drug Targeting of Hypocretin-1 (Orexin-A) to the Central Nervous System
Intranasal Drug Targeting of Hypocretin-1 (Orexin-A) to the Central Nervous System
复制标题
DOI：
10.1002/jps.21604
复制
发表时间：
2009-07-01
影响因子：
3.8
通讯作者：
Frey, William H., II
中科院分区：
文献类型：
--
作者：
Dhuria, Shyeilla V.;Hanson, Leah R.;Frey, William H., II
血脑屏障（BBB）限制了全身给药的治疗剂在中枢神经系统（CNS）的分布。鼻内给药是一种非侵入性方法，将药物沿着嗅觉和三叉神经通路靶向大脑和脊髓，绕过BBB并最大限度地减少全身暴露和副作用。为了评估神经肽（下丘脑泌素-1，HC）的鼻内药物靶向CNS，比较了麻醉大鼠鼻内和静脉输注后血液、CNS组织和外周组织中的药代动力学。尽管鼻内给药的HC血药浓度低10倍，但两种途径的脑浓度相似。与静脉给药相比，鼻内给药后2小时内所有脑区的组织-血液浓度比均显著更高，三叉神经（14倍）和嗅球（9倍）中的比值最高。鼻内给药使药物靶向大脑和脊髓的能力提高了5- 8倍。鼻内给药后约80%的脑浓度-时间曲线下面积是由于从鼻道直接转运所致。鼻内给药可快速将HC靶向至CNS，全身暴露量最小，其中大部分通过不涉及血液和/或脑脊液分布的机制完整到达大脑。(C)2008 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 98：2501-2515，2009
The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS). Intranasal delivery is a noninvasive method that targets drugs to the brain and spinal cord along olfactory and trigeminal neural pathways, bypassing the BBB and minimizing systemic exposure and side effects. To assess intranasal drug targeting of a neuropeptide (hypocretin-1, HC) to the CNS, pharmacokinetics in blood, CNS tissues, and peripheral tissues were compared after intranasal and intravenous infusion to anesthetized rats. Despite a 10-fold lower blood concentration of HC with intranasal administration, both routes resulted in similar brain concentrations. Tissue-to-blood concentration ratios after intranasal administration were significantly greater in all brain regions over 2 h compared to intravenous administration, with the highest ratios in the trigeminal nerve (14-fold) and olfactory bulbs (9-fold). Intranasal delivery increased drug targeting to the brain and spinal cord 5- to 8-fold. Approximately 80% of the area under the brain concentration-time curve following intranasal administration was due to direct transport from the nasal passages. Intranasal delivery rapidly targets HC to the CNS with minimal systemic exposure, most of which reaches the brain intact by mechanisms not involving distribution from the blood and/or cerebrospinal fluid. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2501-2515, 2009