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 (Kp,uu,br) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the Kp,uu,br of discovery compounds with special emphasis on the in-vitro-in-vivo correlation. We also discuss clinical 'translation' of rodent Kp,uu,br and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico Kp,uu,br 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.