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