Assays to predict drug permeation across the blood-brain barrier, and distribution to brain

Drug discovery programmes to target or avoid the brain need to take into account the properties of the blood-brain barrier (BBB). The importance to CNS PK of the free drug concentration in brain is increasingly recognised, and assays for drug discovery programmes are being adjusted accordingly. In vitro models of the BBB continue to play an important role in this process. Good cell-based models using brain endothelium have been developed and validated for mechanistic studies, and some are suitable for medium to high throughput permeability screening and toxicology. Brain homogenate and brain slice methods allow estimation of drug partition into brain. In combination with in silico and in vivo models, the portfolio of methods establishing and predicting CNS drug PK is now very powerful, allowing much more accurate iterative feedback to chemists to optimise compound profiles through the drug discovery and development programme. The advantage of using models based on real BBB cellular anatomy and physiology is that they have the power to reveal and incorporate previously undiscovered properties, such as new transporters, metabolic enzymes and modulation, to form the basis for models mimicking neurological disorders as well as normal function, and to allow physiologically-based pharmacokinetic (PBPK) extrapolation from animal models to humans.