Methods to assess drug permeability across the blood‐brain barrier

Much research has focussed on the development of novel therapeutic agents to target various central nervous system disorders, however less attention has been given to determining the potential of such agents to permeate the blood‐brain barrier (BBB), a factor that will ultimately govern the effectiveness of these agents in man. In order to assess the potential for novel compounds to permeate the BBB, various in‐vitro, in‐vivo and in‐silico methods may be employed. Although in‐vitro models (such as primary cell culture and immortalized cell lines) are useful as a screening method and can appropriately rank compounds in order of BBB permeability, they often correlate poorly to in‐vivo brain uptake due to down‐regulation of some BBB‐specific transporters. In‐vivo models (such as the internal carotid artery single injection or perfusion, intravenous bolus injection, brain efflux index and intracerebral microdialysis) provide more accurate information regarding brain uptake, and these can be complemented with novel imaging techniques (such as magnetic resonance imaging and positron emission tomography), although such methods are not suited to high‐throughput permeability assessment. This paper reviews current methods used for assessing BBB permeability and highlights the particular advantages and disadvantages associated with each method, with a particular focus on methods suitable for moderate‐ to high‐throughput screening.