Molecular Factors Influencing Drug Transfer across the Blood-Brain Barrier

A recently reported approach to the prediction of blood‐brain drug distribution uses the general linear free energy equation to correlate equilibrium blood‐brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; π2H, solute dipolarity or polarizability; α2H and β2H, the hydrogen bond acidity or basicity, and VX, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood‐brain barrier in the rat. The permeability (logPS) of the blood‐brain barrier to a chemically diverse series of compounds was measured using a short duration vascular perfusion method. LogPS data were correlated with calculated solute descriptors, and octanol‐water partition coefficients (logPoct) for comparison. It is shown that a general linear free energy equation can be constructed to predict and interpret logPS values. The utility of this model over other physicochemical descriptors for interpreting logPS and logBB values is discussed.