Introduction: The unbound brain-to-plasma concentration ratio (Kp,uu,brain) is one of the most important indicators for brain penetration in the area of CNS drug discovery and development. Kp,uu,brain can be calculated by combining the total brain-to-plasma concentration ratio (Kp,brain), the brain free fraction (fu,brain) and the plasma free fraction (fu,p).
Aim: This study has three purposes, to calculate Kp,uu,brain from publications in humans, to collect data regarding species differences in Kp,uu,brain and to see whether Kp,uu,brain in humans differs in different brain regions or not.
Materials and Methods: The values of Kp, brain were derived from positron emission tomography (PET), MRS (Magnetic Resonance Spectroscopy), and brain surgery for tumor removal. fu,brain and fu,p were collected from brain homogenate, equilibrium dialysis and ultrafiltration studies.
Results: Data on Kp,brain was sparse in the literature. Kp,uu,brain was calculated for sixteen different drugs in humans. According to the calculation, nine of these sixteen compounds were found to be actively influxed into the brain, six were actively effluxed from the BBB and one had a passive diffusion. Depending on the compound, Kp,uu,brain was higher or smaller in humans compared to mice and rats. Kp,uu,brain for five compounds were calculated for different brain regions. Four compounds had a higher Kp,uu,brain value in almost all other regions than the cerebellum and one had a higher Kp,uu,brain in cerebellum than in the other regions.
Conclusions: No definite conclusion on Kp,uu,brain in humans, species differences in Kp,uu,brain or Kp,uu,brain in different human brain regions could be reached in this study. In view of the importance of Kp,uu,brain in CNS drug discovery and development, more studies on Kp,uu,brain in humans and in the other species are required.