Evaluation of the reliability and applicability of human unbound brain-to-plasma concentration ratios

ABSTRACT Background Blood-brain barrier permeability (BBB P e ) and unbound brain-to-plasma concentration ratio (K p,uu,brain ) are relevant parameters describing the brain uptake potential of compounds. BBB efflux by transporter proteins, mainly MDR-1 and BCRP, is an essential factor determining K p,uu,brain . K p,uu,brain -values are commonly estimated in vivo in rats and monkeys and predicted using in silico methodology. Such estimates can be used to predict corresponding human clinical values. Objective The objective of the study was to evaluate the reliability and applicability of human clinical K p,uu,brain -data for understanding and predictions of brain uptake in man. Methodology K p,uu,brain in rats, monkeys and humans, measured and in silico predicted MDR-1 and BCRP substrate specificities and in silico predicted passive P e were used for the analysis. In silico predictions were done using the ANDROMEDA by Prosilico ADME/PK-prediction software. Results and Discussion Rat and monkey K p,uu,brain -values were highly correlated (R^2=0.74; n=17). Based on this finding a correlation between rat and human K p,uu,brain was expected. However, no correlation between rat and human K p,uu,brain was found (R^2=0.01; n=13). There was no (as also anticipated) correlation between passive P e and human K p,uu,brain (R^2=0.04; n=16) and compounds with measured or predicted efflux did not have lower K p,uu,brain than compounds without efflux. The compound with highest K p,uu,brain in man (2.8) is effluxed and predicted to have high passive P e and has no apparent efflux at the rat BBB. The MDR-1 substrate with highest K p,uu,brain in rat (2.4) has very low K p,uu,brain in man (0.15) is predicted to have high passive P e . Conclusion Results indicate that available human K p,uu,brain -data are too uncertain to be applicable for validation of predictions and understanding of clinical brain uptake of drugs and drug candidates.