Permeation through lipid membranes

A closer inspection of the definition of membrane permeability suggests additional methods to correlate the permeability with other properties of the diffusing species. The permeability, called or P, is related to the equilibrium partition coefficient, K, the diffusion coefficient in the membrane, D, and the thickness of the membrane, L  

This definition of the permeability arises from the equation for steady-state flux through the membrane, N  

Despite their large size, some oligonucleotides can permeate through membranes in artificial liposomes [8]. The half-time for efflux was measured for liposomes with a fixed composition (Table 5.3). 

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Fourth, the oxidant and the reductant resulting from the transmembrane PET should not react with the gaseous products of water cleavage (dihydrogen and dioxygen) which can readily permeate through lipid membranes. 

Fig. 13 This schematic is a depiction of the two models that are associated with ion permeation through lipid membranes containing some HSA (10-hydroxystearic acid) (smaller headgroup and one hydroxylated acyl chain). The lipids are represented by larger headgroups and two acyl chains, and are shown to form two zones that are rich in lipid, and which differ in density (phase domains). Conductivity through zone A is by electrostatic stabilization of ions occur by hydroxyl moieties that exist in domains that are rich in HSA. Conductivity in zone B also involves stabilization of charge by hydroxyl moieties, but it also shows the steric disorder that can exist between domains. This figure is published with permission (Nikolelis et al. 1991)...

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. 

Meanwhile, computational methods have reached a level of sophistication that makes them an important complement to experimental work. These methods take into account the inhomogeneities of the bilayer, and present molecular details contrary to the continuum models like the classical solubility-diffusion model. The first solutes for which permeation through (polymeric) membranes was described using MD simulations were small molecules like methane and helium [128]. Soon after this, the passage of biologically more interesting molecules like water and protons [129,130] and sodium and chloride ions [131] over lipid membranes was considered. We will come back to this later in this section. 

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. 

A second series of papers was published by Stouch and co-workers. Bassolino-Klimas et al. calculated diffusion coefficients for benzene molecules in a DMPC bilayer as function of their location in the bilayer. In later papers this work was extended to study the effect of different temperatures on the preferred locations of benzene molecules and the effect of solute size, studying a drug analog. Simulations of permeation and diffusion through and in bilayers will be described more elaborately in Permeation of Lipid Membranes Molecular Dynamics Simulations. 

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. 

Cell membranes are stmctures containing lipids and proteins as their main components. Many dmg molecules are weak acids or bases and can, therefore, exist as ionized species, depending upon their pATa values and the pH of the environment. One of the more important concepts relating to drug absorption is that ionized species have very low lipid solubility, and are unable to permeate through membranes. Only the non-ionized dmg is usually able to cross membranes. A range of pATa values covered by some common dmgs is shown in Table 4.11. 

Passive Permeation (Diffusion) through the Membrane Lipid Bilayer... 

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