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, 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.
Fischer
H
H
Department of Biophysical Chemistry, Biocenter of the University of Basel, Klingelbergstr, 70, CH-4056 Basel, Switzerland.
Gottschlich
R
R
Seelig
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000388:Air; D000638:Amiodarone / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002090:Butyrophenones / Q000493:pharmacokinetics; D004058:Diffusion; D004294:Domperidone / Q000493:pharmacokinetics; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D008139:Loperamide / Q000493:pharmacokinetics; D008823:Micelles; D008954:Models, Biological; D010880:Piperidines / Q000493:pharmacokinetics; D013499:Surface Properties; D013816:Thermodynamics; D014867:Water
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D008823:Micelles; D010880:Piperidines; D014867:Water; D004294:Domperidone; D008139:Loperamide; C058251:carebastine; D000638:Amiodarone; C058249:ebastine