Blood-brain barrier permeation: Molecular parameters governing passive diffusion

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, CMCD, 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-aw(-1) and CMCD shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, A(D) > 80 Angstrom(2) which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, A(D) congruent to 50 Angstrom(2) which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (A(D) < 50 Angstrom(2)) 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, pi(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)pi(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.