Ionization-specific prediction of blood-brain permeability.

This study presents a mechanistic QSAR analysis of passive blood-brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo log PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log PS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSE < 0.5) and simple physicochemical interpretations (log P and pKa), thus providing a clear route towards property-based design of new CNS drugs.