Lipid membranes permeation

Permeation process of small molecules across lipid membranes studied by molecular dynamics simulations. J. Phys. Chem. 100 (1996) 16729-16738. 

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. 

Sugano, K., Hamada, H., Machida, M., Ushio, H. High throughput prediction of oral absorption improvement of the composition of the lipid solution used in parallel artifidal membrane permeation assay. J. Biomol. Screen. 2001, 6,189-196. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

Figures 4.2b, 4.3b, and 4.4b are log-log speciation plots, indicating the concentrations of species in units of the total aqueous sample concentration. (Similar plots were described by Scherrer [280].) The uppermost curve in Fig. 4.2b shows the concentration of the uncharged species in octanol, as a function of pH. If only uncharged species permeate across lipid membranes, as the pH-partition hypothesis...

Recently in our group, model membrane permeation barriers have been constructed with concentrated phospholipid solutions, 10-74% wt/vol soy lecithin (approximate %w/w lipid composition 24% PC, 18% PE, 12% PI cf. Table 3.1) in dodecane, supported on high-porosity, hydrophobic microfilters. This newly formulated lipid has a net negative charge at pH 7.4, which further increases above pH 8, as the ethanolamine groups deionize. Also tested were 10% wt/vol egg lecithin lipid solutions in dodecane (approximate composition 73% PC, 11% PE,... 

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]. 

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. 

The use of artificial membranes to investigate passive permeation processes has a long history, going back more than 40 years [68], The parallel artificial membrane permeation assay (PAMPA) is an application of the filter-supported lipid membrane system [149] and was first introduced by Kansy and... 

HTS plates permit to determine drug permeability across a cell monolayer with a throughput similar to that of the parallel artificial membrane permeation assay (PAMPA), which measures rate of diffusion across a lipid layer.46 As is the case with PAMPA, the tiny surface area of the filters of the 96-well HTS presents an analytical challenge for compounds with low-to-moderate permeability. 

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. 

Diffusion (A). Lipophilic substances (red dots) may enter the membrane from the extracellular space (area shown in ochre), accumulate in the membrane, and exit into the cytosol (blue area). Direction and speed of permeation depend on the relative concentrations in the fluid phases and the membrane. The steeper the gradient (concentration difference), the more drug will be diffusing per unit of time (Pick s Law). The lipid membrane represents an almost insurmountable obstacle for hydrophilic substances (blue triangles). 

The intestinal wall is covered by a mucus layer. This mucus layer prevents direct contact of the lumenal contents with the epithelial membrane. Mucus can be attached onto the lipid membrane by the aid of agar and hydrophilic filter scaffold [64, 65]. This allows the simultaneous assessment of dissolution and permeation. Food effects were adequately predicted using this method. Lofts son et al. used a cellophane membrane as a surrogate for the mucus layer [66]. 

Dermal and transdermal delivery requires efficient penetration of compounds through the skin barrier, the bilayer domains of intercellular lipid matrices, and keratin bundles in the stratum corneum (SC). Lipid vesicular systems are a recognized mode of enhanced delivery of drugs into and through the skin. However, it is noteworthy that not every lipid vesicular system has the adequate characteristics to enhance skin membrane permeation. Specially designed lipid vesicles in contrast to classic liposomal compositions could achieve this goal. This chapter describes the structure, main physicochemical characteristics, and mechanism of action of prominent vesicular carriers in this field and reviews reported data on their enhanced delivery performance. 

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. 

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. 

Figure 6.19 Schematic representation of the ion permeability modulation for cation-responsive voltammetric sensors based on negatively charged lipid membranes. Com-plexation of the guest cation to the phospholipid receptors causes an increase of the permeation for the anionic marker ion. (Reproduced with permission from Ref. 85.)...

The human body can be basically thought of as a container of water (a polar medium) within which various aqueous compartments are separated by lipid membranes that contain both polar and nonpolar components. The oral route is, for most drugs, the most desirable route for administration into the body because of the ease of selfadministration. However, oral agents must be able to withstand the acidic environment of the stomach and must permeate the gut lining (a mucousal membrane) before entering the bloodstream. 

In intestinal absorption the concentration gradient over the lipid membrane is the driving force for permeation of compounds. The concentration of compound... 

In the case of ionized compounds (weak acids and bases), drug permeation depends on the chemical equilibrium between the ionized and the un-ionized form, both in the delivery system itself and in the lacrimal fluid. In general, un-ionized molecules penetrate lipid membranes more readily than ionized ones. 

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