Centre for Drug Candidate Optimisation - Disciplines

Drug transport across the Blood-Brain Barrier

A major limitation of many potential central nervous system (CNS) drug candidates is their inability to cross the blood-brain barrier (BBB). The BBB is the lining of endothelial cells separating the blood from the brain. While most CNS research focuses on the discovery of new chemical entities to treat various diseases, less attention is given to the physicochemical properties of these entities and the resulting effect on BBB permeability.

The CDCO utilises a mouse or rat brain uptake assay in wild-type and knockout mice to assess brain uptake.  Following intravenous administration to the mice or rats, brain and plasma samples are taken to determine a brain/plasma ratio for the candidate compound. For compounds with a low brain/plasma ratio, additional studies are then conducted in P-glycoprotein deficient (knockout) mice to determine whether P-glycoprotein is a major factor hindering brain uptake (which occurs in many potential CNS drug candidates).

Cell culture models using human brain endothelial cells can be used to provide mechanistic data regarding additional factors affecting compound permeability across the BBB. This model allows an assessment of the inherent compound permeability and can provide insight into the importance of other efflux proteins, endothelial metabolism or plasma protein binding.

Additional in vivo and in situ models are being explored for their utility in assessing aspects related to BBB permeation, including an in situ brain perfusion model and an intracerebral microdialysis model.