Phospholipids water permeability

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

The third class of lipids found in stratum corneum extracts is represented by cholesterol and cholesteryl esters. The actual role of cholesterol remains enigmatic, and no clear reason for its role in the barrier function has been proposed so far. However, it is possible that contrary to what is the role in cell membranes where cholesterol increases close packing of phospholipids, it can act as kind of a detergent in lipid bilayers of long-chain, saturated lipids.30,31 This would allow some fraction of the barrier to be in a liquid crystalline state, hence water permeable in spite of the fact that not only ceramides, but also fatty acids found in the barrier are saturated, long-chain species.28,32... 

The mechanism of inhibition in near-atmospheric CO2 is related to both metabolism and the function of the plasma membrane (24). The permeability of the cellular membrane to dissolved, unhydrated CO2, a neutral molecule, creates disorder and alters the membrane fluidity even at near-atmospheric pressures. However, unlike typical small anaesthetic molecules which alter membrane fluidity, the water permeability of the cell decreases upon contact with CO2 (24). Jones and Greenfield (24) suggest that this unique property of CO2 inhibition is due to the presence of the bicarbonate ion, which may act on the phospholipid head groups and the proteins near the surface of the membrane to alter the surface charge of the cell. 

It was recently shown that for bilayers composed of phospholipids with 18-carbon chains, increasing acyl chain unsaturation increases water permeability to such an extent that di 18 3 PC is five times as permeable to water as 18 0,18 1 PC (Olbrich et al., 2000). Increased water permeation with increased acyl chain unsaturation does not appear to require both chains to be unsaturated, as 18 0,22 6 PC is about four times as permeable as 18 0,18 1 PC, but only about 30% less permeable than di22 6 PC (Husteretal., 1997). 

The interaction between bacterial lipopolysaccharides (EPS) and phospholipid cell membranes was studied by various physical methods of deep rough mutant EPS (ReEPS) of Escherichia coH incorporated in phospholipid bilayers as simple models of cell membranes. SS P-NMR spectroscopic analysis suggested that a substantial part of ReEPS is incorporated into l,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayers when mixed multilamellar vesicles were prepared. Furthermore the lipid lateral diffusion coefficients measurements at various molar ratios of ReEPS/egg-PC/POPG indicated that the incorporated ReEPS reduces the diffusion coefficients of the phospholipids in the membrane. EUV formed by the ReEPS from Salmonella enterica, eventually in mixture with dilauroyl phosphatidylcholine (DEPC), have been prepared and characterized by DES, SANS and EPR. PFGSE NMR measurements have shown that water permeability through the lipid bilayer is low at room temperature. However, above a transition temperature centered at 30-35 °C, the water permeability increases. ... 

Leitch, G. j., Tobias, J. M. Phospholipid-cholesterol membrane-model effects of calcium, potassium, or protamine on membrane hydration, water permeability and electrical resistance. J. cell. comp. Physiol. 63, 225— 232 (1964). 

Four neutral lipid models were explored at pH 7.4 (1) 2% wt/vol DOPC in dode-cane, (2) olive oil, (3) octanol, and (4) dodecane. Table 7.5 lists the effective permeabilities Pe, standard deviations (SDs), and membrane retentions of the 32 probe molecules (Table 7.4). The units of Pe and SD are 10 6 cm/s. Retentions are expressed as mole percentages. Figure 7.22a is a plot of log Pe versus log Kd (octanol-water apparent partition coefficients, pH 7.4) for filters loaded with 2% wt/vol DOPC in dodecane (model 1.0, hlled-circle symbols) and with phospholipid-free dodecane (model 4.0, open-circle symbols). The dashed line in the plot was calculated assuming a UWL permeability (see Section 7.7.6) Pu, 16 x 10-6 cm/s (a typical value in an unstirred 96-well microtiter plate assay), and Pe of 0.8 x 10-6 cm/s... 

Figure 7.22b shows that hydrophilic molecules, those with log Kj < 1, are much more permeable in octanol than in olive oil. The same may be said in comparison to 2% DOPC and dodecane. Octanol appears to enhance the permeability of hydrophilic molecules, compared to that of DOPC, dodecane, and olive oil. This is dramatically evident in Fig. 7.7, and is confirmed in Figs. 7.8c and 7.22b. The mechanism is not precisely known, but it is reasonable to suspect a shuttle service may be provided by the water clusters in octanol-based PAMPA (perhaps like an inverted micelle equivalent of endocytosis). Thus, it appears that charged molecules can be substantially permeable in the octanol PAMPA. However, do charged molecules permeate phospholipid bilayers to any appreciable extent We will return to this question later, and will cite evidence at least for a partial answer. 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

Wohnsland and Faller ([175] performed measurements using a thin (9-10 //in) supported, phospholipid-free hexadecane layer. To validate their model, they used 32 well-characterized chemically diverse compounds. The permeability values obtained with their model could be correlated with known human absorption values if the maximum permeability obtained at different pH was taken into account. However, several disadvantages are related to this method. For hydrophilic drugs, hexadecane by itself has an increased barrier function in comparison with membranes. In addition, the hexadecane layers are not very stable, which makes this assay difficult to apply as a routine screening method. The advantage of this PAMPA setup is that it appears to be a satisfactory substitute for obtaining alkane-water partition coefficients, which are usually very difficult to measure directly, due to the poor solubility of drug molecules in alkanes. 

Dr. Thomas drew our attention to the fact that, although biological membranes are thin in comparison to his preparations, their diffusion constants may be long. I have measured permeability coefficients (transmembrane "diffusion ) for a number of solutes for artificial phospholipid bilayers (liposomes). The values follow and are to be compared for calculated permeabilities for a solute diffusion across a comparable thickness of water. 

Because of their high lipid content, cell membranes are not permeable to highly polar substances and are fluid or "water bed-like" rather than firm or rigid. The relative fluidity is determined largely by the type and abundance of unsaturated fatty acids in the phospholipids. The greater the abundance of unsaturated fatty acids, and the greater the amount of unsaturation within the acids, the greater the fluidity of the membrane. 

How does this shift from fluid to gel state during desiccation cause damage to the membrane, and how does the presence of trehalose or sucrose—water substitutes—prevent this damage As the anecdote about baking technique implies, the crux of the problem occurs when dried cells are rehydrated. It is known from studies of model membranes that when phospholipid bilayers pass through the temperature range over which the gel phase is replaced by the liquid crystalline phase, transient changes in membrane permeability occur (Crowe et al., 1997). The precise mechanism responsible for this transient breakdown in the permeability barrier is not entirely clear, but it... 

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