Fischer H, Gottschlich R, Seelig A
Department of Biophysical Chemistry, Biocenter of the University of Basel, Klingelbergstr, 70, CH-4056 Basel, Switzerland.
J Membr Biol. 1998 Oct 1;165(3):201-11. doi: 10.1007/s002329900434.
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, Kaw, the critical micelle concentration, CMCD, and the cross-sectional area, AD. A three-dimensional plot in which the surface area, AD, is plotted as a function of K-1aw and CMCD shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, AD > 80 A2 which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, AD congruent with 50 A2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (AD < 50 A2) which cross the blood-brain barrier only if applied at high concentrations. It was shown that the lipid membrane-water partition coefficient, Klw, measured previously, can be correlated with the air-water partition coefficient if the additional work against the internal lateral bilayer pressure, pibi = 34 +/- 4 mN/m is taken into account. The partitioning into anisotropic lipid membranes decreases exponentially with increasing cross-sectional areas, AD, according to Klw = const. Kaw exp(-ADpibi/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 pKa > 4 for acids and a pKa < 10 for bases.
通过被动扩散具有临床确定的能够穿过或不能穿过血脑屏障能力的53种化合物，通过表面活性测量以三个参数进行表征，即气-水分配系数Kaw、临界胶束浓度CMCD和截面积AD。一个三维图，其中将表面积AD作为Kaw-1和CMCD的函数绘制，显示出基本上三组化合物：(i) 具有大气-水分配系数和大截面积（AD>80 Å2）的非常疏水的化合物，它们不穿过血脑屏障；(ii) 具有较低气-水分配系数和平均截面积（AD≈50 Å2）的化合物，它们容易穿过血脑屏障；以及(iii) 具有低气-水分配系数（AD<50 Å2）的亲水性化合物，它们仅在高浓度下应用时才穿过血脑屏障。结果表明，如果考虑到对抗内部横向双层压力pibi = 34±4 mN/m的额外功，则先前测量的脂质膜-水分配系数K1w可以与气-水分配系数相关。根据K1w = const·Kaw exp(-ADpibi/kT)，其中kT是热能，进入各向异性脂质膜的分配随截面积AD的增加呈指数下降。因此，对于酸pKa>4且对于碱pKa<10的表面活性分子，在亲水-疏水界面处取向的分子的截面积是膜渗透的主要决定因素。
