灯盏乙素麻醉大鼠鼻腔给药脑内靶向性评价

Evaluation of brain-targeted trendence of scutellarin nasal administration

目的:探索灯盏乙素利用鼻腔嗅觉区的鼻-脑通道进行鼻脑靶向给药的可行性。方法:以注射给药为对照,于灯盏乙素鼻腔给药后一定时间用小脑延髓池穿刺术采集大鼠脑脊液,股动脉插管取血,125I标记法测定其在大鼠脑脊液、脑组织和血中药物含量,梯形法计算药物动力学参数;以AUCbrain/AUCplasma为指标评价脑靶向性。结果:大鼠鼻腔给药后灯盏乙素的脑内分布具有组织差异,经鼻腔吸收后5～15 min,嗅球即达峰值,在30～60 min时其在各脑组织中的药浓均达到峰值,其中,嗅球(574.8±205.9)ng.g-1、嗅区(323.4±128.3)ng.g-1、脑脊液(123.2±29.3)ng.g-1。灯盏乙素鼻腔给药后的脑部药浓分布如下:嗅球嗅区>脑脊液>小脑>延髓>大脑;相等剂量给药时,灯盏乙素鼻腔给药后嗅球、嗅区、CSF的AUC0～240分别为静注的5.54,5.07,5.51倍,其他脑组织的AUC0～240均大于静注。灯盏乙素鼻腔给药后各脑组织的AUCbrain/AUCplasma均显著高于静注给药,5 min时嗅球、CSF、大脑的AUCCR/AUCplasma值分别是静注的56.93,30.45,6.14倍。结论:灯盏乙素鼻腔给药后可能经以下吸收通路直接转运入脑:经鼻腔嗅黏膜吸收进入蛛膜下腔的嗅球,然后相继进入嗅区、CSF、大脑、小脑等部位,嗅球是药物分子经鼻腔入脑的必经之路。与静注给药相比,灯盏乙素鼻腔给药具有明显的脑靶向性。

Objective： To evaluate the feasibility of developing brain-targeted nasal delivery system of scutellarin by the passage between nase and brain in nasal olfactory area.Method： The samples of cerebrospinal fluid（CSF） and blood were prepared by cranial puncture and femoral artery catheterization methods respectively according to the certain sampling time after drug administered.The scutellarin concentration of samples were determined by 125I marked method.Pharmacokinetic parameters were calculated by trapezoidal rule.The brain-targeted trendence were evaluated by the value of the index AUCbrain/AUCplasma.Result： The distribution of scutellarin in brain following intranasal administration was different between tissues.Drug concentration in olfactory bulb achieved to peak at 5-15 min after intranasal administration,while in brain tissue was 30-60 min.Above all,peak concentration in olfactory bulb and olfactory region respectively were（574.8±205.9）,（323.4±128.3） ng·g^-1,both are higher than CSF,which is（123.2±29.3） ng·g^-1.Moreover,the distribution of scutellarin given by intranasally in brain was： olfactory bulb（OB） ≥ olfactory region（OR） cerebrospinal fluid（CSF） cerebellum（CB） medulla oblongata（MO） cerebrum（CR）;AUC0-240 of olfactory bulb,olfactory region and CSF after scutellarin intranasal administration were 5.54,5.07 and 5.51 times of that after intravenous injection,respectively.And the AUC0-240 of other brain tissues after intranasal administration were also higher than that after intravenous injection.AUCbrain tissue/ AUCplasma of every brain tissues by intranasally are all higher than that by intravenously remarkably.For instance,5min after intranasal administration,the value of AUCCSF/ AUCplasma,AUCOB/AUCplasma and AUCCR/AUCplasma were 30.34,56.93,and 6.14 times of that by intravenously.Conclusion： Part of scutellarin could be straightly transported into brain by the intranasal administration.Its absorption pathway was： the molecule of Scutellarin throughed olfactory mucosa in nasal cavity into olfactory bulb in arachno-hypostegal cavity,and then entered into olfactory region,CSF,cerebrum and cerebellum gradually.It showed that olfactory bulb was the only way for drug molecule to go through nasal cavity into brain.It had a significant trendence of brain-targeted when compared to oral administration and intravenous injection,which indicated a certain feasibility to develop a brain-targeted nasal delivery system for scutellarin.