基于脑局部给药的药物分布与清除大鼠模型的建立

Establishment of a Rat Model of Drug Distribution and Clearance for Brain Localized Delivery

目的应用磁共振分子探针示踪技术,研究大鼠深部脑组织间隙(interstitial space,ISS)内物质转运与脑组织液引流的规律。结合多孔介质经典扩散方程,建立大鼠脑局部给药的药物分布与清除动力学模型。方法 24只SD大鼠随机分为尾状核、丘脑、中脑黑质3组(n=8)。将细胞外示踪剂惰性分子探针钆喷酸葡胺(gadolinium-diethylenetriaminepentaacetic acid,Gd-DTPA)2μl分别导入三个脑区细胞外间隙,利用磁共振成像(MRI)动态采集探针在大鼠脑ISS内的分布与清除过程。通过图像后处理获取ISS内示踪分子在大鼠全脑分布的最大分布容积比(Vdmax%)及半衰期(t1/2)。应用经典扩散方程,测量ISS有效扩散系数(D*)、清除率(k’)与局部迂曲度(λ)。结合上述结果及经典扩散方程,建立大鼠脑组织间隙内药代动力模型。结果示踪分子在大鼠不同脑区ISS内的转运分布区域、清除速率各不相同。尾状核Vdmax%和t1/2大于丘脑和黑质(P=0.000)。黑质区D*小于尾状核、丘脑(P=0.021),黑质ISS内迂曲度最大(P=0.280)。丘脑局部k’大于尾状核和黑质区域(P=0.000)。结论钆喷酸葡胺(Gd-DTPA)在大鼠深部脑组织内分布呈分区特征,各分区内药物的分布与清除速率各不相同。脑局部给药需考虑脑内ISS的解剖分区以及各个脑分区的物质转运与脑组织液流动参数特征。

Objective To explore the drainage process of brain interstitial fluid（ISF） and transport property in interstitial space（ISS） in rat deep brain tissue by tracer-based magnetic resonance imaging（MRI）.On the basis of classical diffusion equation in porous media,to establish distribution and clearance model for local drug administration of brain.Methods A total of 24 Sprague Dawley rats were randomly divided into three groups according to the injection points：caudate putamen（CPu）,thalamus（T）,and substantia nigra（SN）,with 8 rats in each group.The brain ISF was traced with a MRI contrast agent,2 μl gadolinium diethylenetriaminepentaacetic acid（Gd-DTPA）,which was injected into the brain ISS.Three-dimensional dynamic distribution of the probes was displayed and quantitative calculations were completed by self-developed image processing software.The distribution ratio referring tracers＇ maximum volume of the whole brain（Vdmax%） and the half-life time（t1 /2） were obtained.ISS microscopic diffusion parameter（D＊）,clearance rate（k＇）,and local tortuosity（λ） were measured based on classical diffusion equation.Hence,we established pharmacokinetics model of the brain ISS.Results The transport distribution area and clearance rates of tracer molecule varied in ISS of different brain regions.The Vdmax% and t1 /2of the caudate putamen were greater than those of the thalamus and substantia nigra（P = 0.000）.The D＊in substantia nigra was less than that in caudate putamen and thalamus（P = 0.021）,deriving the greatest λ in substantia nigra（P = 0.280）.The k＇in thalamus was greater than that in caudate putamen and substantia nigra（P = 0.000）.Conclusions Drug distribution in the brain ISS is partitioned,with drug distribution and clearance rates varying within each sub-region.Topical brain anatomy in each brain partition and fluid flow parameter characteristics of partitioned ISS should be considered in local brain delivery.