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

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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