Transport Studies Using Blood-Brain Barrier In Vitro Models: A Critical Review and Guidelines
Permeation is one of the most evaluated parameters using preclinical in vitro blood-brain barrier models, as it has long been considered to be one of the major factors influencing central nervous system drug delivery. Blood-brain barrier permeability can
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Contents 1 Introduction 2 In Vitro Permeability Measurements 2.1 Apparent Permeability Coefficient 2.2 Endothelial Permeability Coefficient 2.3 Efflux Ratio as a Measurement of Active Efflux 3 Permeability Studies to Measure Barrier Tightness 3.1 Factors Influencing BBB Permeability Results 3.2 Importance of Recovery Values 3.3 Importance of the Materials Used in the Permeability Assay 3.4 Influence of Mechanical Forces
Ana R. Santa-Maria and Marjolein Heymans contributed equally to this work. A. R. Santa-Maria Institute of Biophysics, Biological Research Centre, Szeged, Hungary Doctoral School of Biology and Department of Biotechnology, University of Szeged, Szeged, Hungary M. Heymans · M. Culot (*) · F. Gosselet Laboratoire de la Barrière Hémato-Encéphalique (LBHE), UR 2465, University Artois, Lens, France e-mail: [email protected] F. R. Walter Institute of Biophysics, Biological Research Centre, Szeged, Hungary Department of Biotechnology, University of Szeged, Szeged, Hungary M. A. Deli (*) Institute of Biophysics, Biological Research Centre, Szeged, Hungary e-mail: [email protected] W. Neuhaus (*) Austrian Institute of Technology, Center Health and Bioresources, Vienna, Austria e-mail: [email protected] # Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_394
A. R. Santa-Maria et al. 3.5 Plasma Protein Binding and Brain Tissue Binding 3.6 Example of Normalization: Diazepam 4 Transendothelial Electrical Resistance Measurements 5 Conclusion References
Abstract
Permeation is one of the most evaluated parameters using preclinical in vitro blood-brain barrier models, as it has long been considered to be one of the major factors influencing central nervous system drug delivery. Blood-brain barrier permeability can be defined as the speed at which a compound crosses the brain endothelial cell barrier and is employed to assess barrier tightness, which is a crucial feature of brain capillaries in vivo. In addition, it is used to assess brain drug penetration. We review traditionally used methods to assess blood-brain barrier permeability in vitro and summarize often neglected in vivo (e.g., plasma protein and brain tissue binding) or in vitro (e.g., culture insert materials or methodology) factors that influence this property. These factors are crucial to consider when performing BBB permeability assessments, and especially when comparing permeability data obtained from different models, since model diversification significantly complicates inter-study comparisons. Finally, measuring transendothelial electrical resistance can be used to describe blood-brain barrier tightness; however, several parameters should be considered while comparing these measurements to the blood-brain barrier permeability to paracellular markers. Keywords
Brain capillary endothelial cells · Cell layer tightness · Drug transport · Paracellular transport · Penetration · TEER
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Introduction
Until a decade ago, the focus of many central nervous system (CNS) drug programs was
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