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

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.

Vascularizing the brain in vitro

“…Indeed, the TEER measurements for monoculture are reported to be less than other culture models. The barrier tightness can be improved by adding glucocorticoids dexamethasone and hydrocortisone, which increase most TJ protein expressions, namely occludin, claudin-1, claudin-12, ZO-1, and VE-cadherin ( Hoheisel et al., 1998 ; Neumaier et al., 2021 ; Schrot et al., 2005 ). The increase of these proteins correlates with the increase of TEER and reduction of permeability.…”

“…To replicate the CNS in vitro is an interdisciplinary field that has drawn much attention during the last decade ( Bhalerao et al., 2020 ; Hopkins et al., 2015 ; Keep et al., 2021 ; Lee and Leong, 2020 ; Neumaier et al., 2021 ; Teixeira et al., 2020 ). The neuronal tissue, the vasculature, and the interstitial system are the three main components that make up the brain.…”

Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

“…While logBB is a logarithmic expression for the equilibrium ratio of the concentration of a compound in brain to that in plasma [31], logPS is a measure for the rate of brain penetration [36]. Similar to logD, the significance of both molecular descriptors is controversially discussed [37][38][39][40][41]; however, since these descriptors represent only a part of our physico-chemical property analysis, their use has been deemed appropriate.…”

Madin-Darby Canine Kidney (MDCK) Cell line permeability of Curcumin loaded Phycocyanin nanosponges - In-Vitro study

“…Blood-Brain barrier (BBB) is a protective and dynamic wall that restricts the entry of any harmful substance. This barrier system protects the brain from xenobiotics which is also a major obstacle to delivering drugs into the central nervous system (Pardridge 2005;Kadry et al 2020;Neumaier et al 2021;Sanchez-Dengra et al 2021). Efflux transporters play a vital role in fluxing the drugs and limit the BBB penetration (Loscher and Potschka 2005;Neumaier et al 2021;Sanchez-Dengraetal 2021).…”

“…This barrier system protects the brain from xenobiotics which is also a major obstacle to delivering drugs into the central nervous system (Pardridge 2005;Kadry et al 2020;Neumaier et al 2021;Sanchez-Dengra et al 2021). Efflux transporters play a vital role in fluxing the drugs and limit the BBB penetration (Loscher and Potschka 2005;Neumaier et al 2021;Sanchez-Dengraetal 2021). The Key barriers that interfere with the permeation of drugs are brain microvascular endothelial cells (BMECs) with tight junctional proteins & metabolizing enzymes like cytochrome P450 and transport barriers like P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and organic anion transporting polypeptide.…”