Strategies to optimize brain penetration in drug discovery.

The kinetics of brain penetration has two components, extent and rate. Achieving a high extent of brain penetration is an important focus for central nervous system (CNS) drug discovery. Optimal brain penetration can be achieved by reducing efflux transport at the blood-brain barrier (BBB), and it is critical to ensure that a high total brain/plasma ratio (the most commonly used parameter for measuring brain penetration) is due to efflux transport activity at the BBB and not related to high non-specific brain tissue binding or low plasma binding. Rapid brain penetration is essential for those drugs that require fast onset of action in the CNS. This can be achieved by increasing passive permeability and reducing brain tissue binding.