Development of a drug delivery system using the receptors located on the cerebral microvessels : An approach based on the physiological pharmacokinetio model.

本研究的最终目的是利用位于脑微血管上的受体开发一种药物释放系统。在本研究中，我们分析了亲水性药物在中国的处置情况。中枢神经系统(CNS)，使用基于生理学的药代动力学(PK)模型。作为模型化合物，我们使用了β-内酰胺类抗生素，因为我们已经表明这些药物的受体(S)(转运载体(S))的存在。研究了静脉或静脉给药后[14C]头孢地齐在中枢神经系统的代谢情况。在此基础上，对实验数据进行了分析。PK模型包括TH跨血脑屏障(BBB)和血脑脊液屏障(BCSFB)的转运过程，以及在脑ECF中的扩散过程。我们用偏微分方程描述了这些过程，并得到了拉普拉斯变换的解。实验数据与该解进行了拟合。The f…在实验数据上叠加了更多的线条。生理/解剖参数的计算值与报道的值一致。这些结果表明了该PK模型的合理性。此外，基于前面描述的概念，我们分析了体内(静脉注射后从脑脊液中清除配体)和体外(通过分离的脉络丛积累配体)的研究结果，发现这些结果之间有很好的相关性。这些结果表明：(1)脉络丛是脑脊液中β-内酰胺类抗生素转运的主要部位；(2)分离的脉络丛可作为预测这些药物体内转运特性的有用工具。基于此PK模型的模拟研究表明，跨BCSFB(从血液到脑脊液)的转运清除的改善导致了脑实质中药物浓度的增加，这表明跨BCSFB的药物输送系统的发展可能对将药物输送到脑实质具有重要意义。较少

The final purpose of the present study is to develop a drug delivery system using the receptors located on the cerebral microvessels. In the present study, we analyzed the disposition of hydrophilic drugs in. the central nervous system (CNS), using a physiologically based pharmacokinetic (PK) model. As model compounds, we used beta-lactam antibiotics, since we have indicated the presence of the receptor (s) (transport carrier(s)) for these drugs. The disposition of [14C] cefodizime, a non-metabolizable antibiotic, in the CNS after i. v. or i. c. v. administration was examined. Then, these experimental data were analyzed based on the. PK model, in which th& transport processes across the blood-brain (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB), as well as the diffusion process in the brain ECF are included. We described these processes using a partial differential equation and obtained a Laplace transformed solution. The experimental data were fitted to this solution. The f … More itted line superimposed on the experimental data. The calculated values for the physiological/anatomical parameters were consistent with the reported values. These results indicate the propriety of this PK model. Furthermore, based on the concept described previously, we analyzed the results of in vivo (elimination of ligands from the CSF after i. c. v. administration) and in vitro (accumulation of ligands by the isolated choroid plexus) studies, and found that a good relationship between these results. These results suggest (1) that the choroid plexus is the predominant site for the transport of beta-lactam antibiotics from the CSF and (2) that isolated choroid plexus can be a useful tool to predict the in vivo transport properties of these drugs. A simulation study based on this PK model suggested that the improvement of the transport clearance across the-BCSFB (from blood to CSF) results in the increase in the drug concentration in the brain parenchyma, suggesting the development of a drug delivery system across the BCSFB may be significant to deliver drugs into the brain parenchyma. Less