Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

Abstract

Abstract. 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 Å 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 ≅ 50 Å 2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (A D < 50 Å 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, bi ‫ס‬ 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 ‫ס‬ const. K aw exp(−A D 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.

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…However, the molecular weight of 268 Da of LB100 is within the often-cited figure of 400 Da as the cut-off for free diffusion of lipid-soluble small molecules into the CNS. 76 Furthermore, as demonstrated by Chang et al, 152 LB100 is not subjected to ABC efflux transporters, which are often responsible for multidrug resistance in the delivery of therapeutic compounds to the brain. 153 As such, it is clear that additional study of LB100 against intracranial tumors is needed.…”

“…Unlike LB100, LB102 is lipidsoluble, a property that is required for diffusion of small molecules across the blood brain barrier. 76 As such, in future studies of intracranial tumors, it may be more appropriate to utilize LB102 over LB100 in the targeting of PP2A.…”

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

“…Previous pharmacokinetic studies have shown that bumetanide and the chemically similar loop diuretics furosemide and torasemide distribute only in the extracellular fluid, indicating that they do not readily cross plasma membranes (Chen, 1996;Friedel and Buckley, 1991). Also, in a study of chemical properties determining the ability of various drugs to cross the BBB, furosemide did not cross the barrier (Fischer et al, 1998). Thus, although bumetanide should readily distribute in extracellular fluid outside the brain, it should not penetrate into the brain in the presence of an intact BBB.…”

Evaluation of antitubercular drug insertion into preformed dipalmitoylphosphatidylcholine monolayers

“…All the antitubercular drugs had a concentration dependent behavior. Properties like hydrophobicity, molecular weight, ionization affect membrane partition coefficient of drugs while factors like molecular weight give an approximation of molecular size [24,25] which can have effect on membrane insertion.…”