, Volume 165, Issue 3, pp 201-211

Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

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53 compounds with clinically established ability to cross or not to cross the blood-brain barrier by passive diffusion were characterized by means of surface activity measurements in terms of three parameters, i.e., the air-water partition coefficient, K aw , the critical micelle concentration, CMC D , and the cross-sectional area, A D . A three-dimensional plot in which the surface area, A D , is plotted as a function of K −1 aw and CMC D shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, A D > 80 Å2 which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, A D ≅ 50 Å2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (A D < 50 Å2) which cross the blood-brain barrier only if applied at high concentrations. It was shown that the lipid membrane-water partition coefficient, K lw , measured previously, can be correlated with the air-water partition coefficient if the additional work against the internal lateral bilayer pressure, π bi = 34 ± 4 mN/m is taken into account. The partitioning into anisotropic lipid membranes decreases exponentially with increasing cross-sectional areas, A D , according to K lw =const. K aw exp(−A D π bi /kT) where kT is the thermal energy. The cross-sectional area of the molecule oriented at a hydrophilic-hydrophobic interface is thus the main determinant for membrane permeation provided the molecule is surface active and has a pK a > 4 for acids and a pK a < 10 for bases.