Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems.

Felix Neumaier,Bernd Neumaier,Boris D Zlatopolskiy

doi:10.3390/pharmaceutics13101542

Abstract

Delivery of most drugs into the central nervous system (CNS) is restricted by the blood–brain barrier (BBB), which remains a significant bottleneck for development of novel CNS-targeted therapeutics or molecular tracers for neuroimaging. Consistent failure to reliably predict drug efficiency based on single measures for the rate or extent of brain penetration has led to the emergence of a more holistic framework that integrates data from various in vivo, in situ and in vitro assays to obtain a comprehensive description of drug delivery to and distribution within the brain. Coupled with ongoing development of suitable in vitro BBB models, this integrated approach promises to reduce the incidence of costly late-stage failures in CNS drug development, and could help to overcome some of the technical, economic and ethical issues associated with in vivo studies in animal models. Here, we provide an overview of BBB structure and function in vivo, and a summary of the pharmacokinetic parameters that can be used to determine and predict the rate and extent of drug penetration into the brain. We also review different in vitro models with regard to their inherent shortcomings and potential usefulness for development of fast-acting drugs or neurotracers labeled with short-lived radionuclides. In this regard, a special focus has been set on those systems that are sufficiently well established to be used in laboratories without significant bioengineering expertise.

Highlights

To maintain normal brain homeostasis, the exchange of many substances between blood and the central nervous system (CNS) is restricted by two dedicated biological barriers, the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB)
The BBB is primarily formed by the endothelium that makes up the wall of all brain capillaries, while the BCSFB is located at the level of the choroid plexus and is formed by the tight epithelium lining the ventricles
Robust estimates for the rate of BBB penetration can often be obtained with suitable in vitro BBB models, they are recognized as poor predictors for the success of CNS drugs that are dosed continuously

Summary

Introduction

To maintain normal brain homeostasis, the exchange of many substances between blood and the central nervous system (CNS) is restricted by two dedicated biological barriers, the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB). 10–20 m2 or 100–240 cm2 /g brain in humans [1,2,3,4,5,6], the BBB is almost 5000-fold larger than the BCSFB, which makes it the primary interface for exchange of compounds between circulation and CNS [7]. It is crucial for import of nutrients and export of metabolites from the CNS, the BBB restricts delivery of most drugs to the brain [2] and represents a significant bottleneck in the development of novel CNS-targeted therapeutics or neurotracers for imaging techniques like positron emission tomography (PET). A number of in vitro approaches have been introduced to complement or replace in vivo

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