CHAPTER 17: Crossing the Blood-brain Barrier – Methods for Evaluating CNS Exposure

Assessment of CNS penetration is an integral part of psychiatric drug discovery. Compounds that are freely permeable and are not subject to active efflux from the CNS are likely to have free brain levels comparable to free plasma concentrations. In such cases, improvement of CNS exposure will focus on optimizing plasma pharmacokinetics. Experimental approaches are outlined for confirming whether the free drug equilibrium assumption holds true for a particular compound series. Where low CNS exposure (relative to plasma) is seen, a strategy is outlined for improving CNS exposure using in vitro and in vivo tools. Additionally, output from the rat serial CSF model is explored to demonstrate the care needed in interpreting such data. Also discussed are approaches that have been in common use but may not contribute to successful CNS drug discovery.