Hurdles with Using In Vitro Models to Predict Human Blood-brain Barrier Drug Permeability: A Special Focus on Transporters and Metabolizing Enzymes

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.