Lipid bilayers permeation

Most drug substances and substances of interest to health and environmental risk assessors enter cells by passive permeation (diffusion). In this process, a substance dissolves in the membrane lipid bilayer, permeates through the membrane, and enters into the cytoplasm of the cell. The substance thus must be soluble in lipids. The process is passive because the rate and extent to which a substance will enter a cell by this means depends on its concentration outside and inside the cell. The net movement is from the region of higher concentration to that of lower concentration. Unlike the cell membrane, which is chiefly lipid, the extracellular and intracellular spaces separated by the membrane are aqueous. The higher the concentration of substance outside of the cell, and the more soluble the substance in the membrane lipid bilayer, the greater will be the tendency for the substance to diffuse across the membrane and enter the cytoplasm. The rate and extent of diffusion will decrease as the concentration of the substance inside the cell increases until, eventually, equilibrium is reached. 

As for the lipid bilayer permeation, several phenomena could be responsible, namely dissolution of the hydrophobic part ofthe polycation... 

This review addresses the issues of the chemical and physical processes whereby inorganic anions and cations are selectively retained by or passed through cell membranes. The channel and carrier mechanisms of membranes permeation are treated by means of model systems. The models are the planar lipid bilayer for the cell membrane, Gramicidin for the channel mechanism, and Valinomycin for the carrier mechanism. 

Thomae, A. V., Wunderli-Allenspach, H., Kramer, S. D. Permeation of aromatic carboxylic adds across lipid bilayers the pH-partition hypothesis revisited. Biophys. J. 2005, 89,1802-1811. 

III. PERMEATION OF SMALL MOLECULES ACROSS LIPID BILAYERS ROLE OF BILAYER STRUCTURE... 

FIG. 13 A schematic illustration of the effects of the free surface area of lipid bilayer membranes on the permeation of two permeants with the same molecular volume, but different cross-sectional areas, (a) A lower free surface area, (b) A higher free surface area. 

Walter, A. Gutknecht, J., Monocarboxylic acid permeation through lipid bilayer membranes, J. Membr. Biol. 77, 255-264 (1984). 

The lipid bilayer arrangement of the plasma membrane renders it selectively permeable. Uncharged or nonpolar molecules, such as oxygen, carbon dioxide, and fatty acids, are lipid soluble and may permeate through the membrane quite readily. Charged or polar molecules, such as glucose, proteins, and ions, are water soluble and impermeable, unable to cross the membrane unassisted. These substances require protein channels or carrier molecules to enter or leave the cell. 

Models of lipid bilayers have been employed widely to investigate diffusion properties across membranes through assisted and non-assisted mechanisms. Simple monovalent ions, e.g., Na+, K+, and Cl, have been shown to play a crucial role in intercellular communication. In order to enter the cell, the ion must preliminarily permeate the membrane that acts as an impervious wall towards the cytoplasm. Passive transport of Na+ and Cl ions across membranes has been investigated using a model lipid bilayer that undergoes severe deformations upon translocation of the ions across the aqueous interface [126]. This process is accompanied by thinning defects in the membrane and the formation of water fingers that ensure appropriate hydration of the ion as it permeates the hydrophobic environment. 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

In this review, we have presented a molecular picture of the lipid bilayer system in relation to its permeation properties, as it appears from simulations and from self-consistent field calculations. Of course, it was not possible to go into all the details. In fact, the practicalities are always much more complicated, and the fine details are only of interest to the experts. 

Mitragotri, S., Johnson, M. E., Blankschtein, D. and Langer, R. (1999). An analysis of size selectivity of solute partitioning, diffusion, and permeation across lipid bilayers, Biophys. J., 77, 1268-1283. 

The successful application of in vitro models of intestinal drug absorption depends on the ability of the in vitro model to mimic the relevant characteristics of the in vivo biological barrier. Most compounds are absorbed by passive transcellular diffusion. To undergo tran-scellular transport a molecule must cross the lipid bilayer of the apical and basolateral cell membranes. In recent years, there has been a widespread acceptance of a technique, artificial membrane permeation assay (PAMPA), to estimate intestinal permeability.117118 The principle of the PAMPA is that, diffusion across a lipid layer, mimics transepithelial permeation. Experiments are conducted by applying a drug solution on top of a lipid layer covering a filter that separates top (donor) and bottom (receiver) chambers. The rate of drug appearance in the bottom wells should reflect the diffusion across the lipid layer, and by extrapolation, across the epithelial cell layer. 

We mention a few studies on polar and charged molecule-lipid interactions, as their permeation involves defect and pore formation, which involves lipid-lipid interactions. A detailed examination of small molecule-lipid interactions is beyond the scope of this chapter [74], We have shown that a large component of the free energy of small polar or charged molecule partitioning into lipid bilayers is due to the cost of forming a defect [75]. 

Xiang, T., Xu, Y. and Anderson, B.D. (1998) The barrier domain for solute permeation varies with lipid bilayer phase structure. Journal of Membrane Biology, 165, 77-90. 

The permeability of solutes across lipid bilayers is a product of the partition coefficient and the transverse diffusion coefficient [30]. Bilayer polymerization can alter solute diffusion by modifying either or both of these processes. In order to examine the effect of polymerization on bilayer permeability a nonionic solute of moderate permeability, [3H-glucose], was encapsulated in the vesicles prior to polymerization, removed from the exterior after polymerization, and its permeation across the bilayer was measured periodically [31]. Quantitative measurements of the 3H-glucose leakage revealed that the formation of linear polymer chains from methacryloyl lipids reduced the permeability coefficient to 0.3 to 0.5 of that of the unpolymerized lipid vesicles. A larger reduction (two orders of magnitude) was only found when crosslinked polymer networks were formed [31]. 

I would like to extend Prof. Simon s characterizations of these beautiful new molecules to include a description of the effects on lipid bilayers of his Na+ selective compound number 11, which my post-doctoral student, Kun-Hung Kuo, and I have found to induce an Na+ selective permeation across lipid bilayer membranes [K.-H. Kuo and G. Eisenman, Naf Selective Permeation of Lipid Bilayers, mediated by a Neutral Ionophore, Abstracts 21st Nat. Biophysical Society meeting (Biophys. J., 17, 212a (1977))]. This is the first example, to my knowledge, of the successful reconstitution of an Na+ selective permeation in an artificial bilayer system. (Presumably the previous failure of such well known lipophilic, Na+ complexing molecules as antamanide, perhydroan-tamanide, or Lehn s cryptates to render bilayers selectively permeable to Na+ is due to kinetic limitations on their rate of complexation and decomplexation). 

---