Hurdles in Predicting Human Blood-Brain Barrier Drug Permeability Using Animal and In Vitro Models: A Special Focus on Transporters and Metabolizing Enzymes

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Journal Title, Volume, Page: 
Curr Drug Metab. 2013 Jan;14(1):120-36
Year of Publication: 
2013
Authors: 
Ramzi Shawahna
Neuropsychopharmacologie des addictions (CNRS UMR 8206), Université Paris Descartes, Faculté de Pharmacie, Paris, France
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
Xavier Decleves
Neuropsychopharmacologie des addictions (CNRS UMR 8206), Université Paris Descartes, Faculté de Pharmacie, Paris, France
Jean-Michel Scherrmann
Neuropsychopharmacologie des addictions (CNRS UMR 8206), Université Paris Descartes, Faculté de Pharmacie, Paris, France
Preferred Abstract (Original): 

The penetration of drugs into the human brain through the blood-brain barrier (BBB) is a major obstacle limiting the development of successful neuropharmaceuticals. This restricted permeability is due to the delicate intercellular junctions, efflux transporters and metabolizing enzymes present at the BBB. The pharmaceutical industry and academic research relies heavily on permeability studies conducted in animals and in vitro models of the BBB. This text reviews the available animal and in vitro BBB models with special emphasis on the situation in freshly isolated human brain microvessels and the unique tightness between brain endothelial cells, drug transport pathways and metabolic capacity. We first outline the delicate structure of the intercellular junctions and the particular interaction between the brain endothelial cells and other components of the neurovascular unit. We then examine the differences in transporters and metabolizing enzymes between species and in vitro systems and those found in isolated brain microvessels. Finally, we review the possibilities of benchmarking in vitro models of the BBB in terms of gene and protein expression.

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