Abstract
One of the major reasons why central nervous system (CNS)-drug development has been challenging in the past, is the barriers that prevent substances entering from the blood circulation into the brain. These barriers include the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), blood-cerebrospinal fluid barrier (BCSFB), and blood-arachnoid barrier (BAB), and they differ from each other in their transporter protein expression and function as well as among the species. The quantitative expression profiles of the transporters in the CNS-barriers have been recently revealed, and in this review, it is described how they affect the pharmacokinetics of compounds and how these expression differences can be taken into account in the prediction of brain drug disposition in humans, an approach called pharmacoproteomics. In recent years, also structural biology and computational resources have progressed remarkably, enabling a detailed understanding of the dynamic processes of transporters. Molecular dynamics simulations (MDS) are currently used commonly to reveal the conformational changes of the transporters and to find the interactions between the substrates and the protein during the binding, translocation in the transporter cavity, and release of the substrate on the other side of the membrane. The computational advancements have also aided in the rational design of transporter-utilizing compounds, including prodrugs that can be actively transported without losing potency towards the pharmacological target. In this review, the state-of-art of these approaches will be also discussed to give insights into the transporter-mediated drug delivery to the CNS.
Highlights
The discovery and development of new drugs acting on the central nervous system (CNS) is a crucial subject in today’s aging society
Several reports are showing a fairly good correlation between Kp,uu,brain and Kp,uu,csf [32–34], the results shown in the dog [30] prove clearly that drug concentration in the cerebrospinal fluid (CSF) does not reflect the blood-brain barrier (BBB) transport function
We have demonstrated that it is possible to predict the concentration of unbound drugs in the brain using a mouse model based on the following theory (Eq 4) (Fig. 3A) [13]: Kp,uu,brain = 1 + ((in vitro MDR1 efflux ratio) − 1) × 1 MDR1 protein expression level in brain microvessels [4]
Summary
The discovery and development of new drugs acting on the central nervous system (CNS) is a crucial subject in today’s aging society. Transporter Protein Expression per Surface Area of the Barrier (fmol/cm2) Is an Important Unit for the Prediction of Kp,uu,brain
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