Prediction of Brain:blood Unbound Concentration Ratios in CNS Drug Discovery Employing in Silico and in Vitro Model Systems

Recent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (K) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the K of discovery compounds with special emphasis on the in-vitro-in-vivo correlation. We also discuss clinical 'translation' of rodent K and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico K models built on larger datasets of high quality, calibration and deeper understanding of experimental in vitro transporter systems, and better understanding of blood-brain barrier transporters and their in vivo relevance aside from P-gp and BCRP.