Membranes, artificial

1987) and lobster nerve 16 vs 10 pS (Castillo et al. 1992). Veratridine-modified channels in natural membranes show lower conductances (see previous section), most probably because they have been determined at lower (natural) cation concentrations. In some preparations conductance sublevels are found in the presence of veratridine, for example, in eel electroplax (Duch et al. 1989) this may, however, result from unresolved rapid channel closings. Also, some rat brain channels modified by vera- 

Due to their better biomimetic properties, phospholipids have been proposed as an alternative to 1-octanol for lipophiiicity studies. The use of immobilized artificial membranes (lAM) in lipophiiicity determination was recently reviewed and we thus only briefly summarize the main conclusions [108]. lAM phases are silica-based columns with phospholipids bounded covalently. lAM are based on phosphatidylcholine (PC) linked to a silica propylamine surface. Most lipophiiicity studies with lAM were carried out using an aqueous mobile phase with pH values from 7.0 to 7.4 (log D measurements). Therefore, tested compounds were neutral, totally or partially ionized in these conditions. It was shown that the lipophiiicity parameters obtained on I AM stationary phases and the partition coefficients in 1-octanol/water system were governed by different balance of intermolecular interactions [109]. Therefore the relationships between log kiAM and log Poet varied with the class of compounds studied [110]. However, it was shown that, for neutral compounds with log Poet 1, a correspondence existed between the two parameters when double-chain lAM phases (i.e., lAM.PC.MG and IAM.PC.DD2) were used [111]. In contrast, in the case of ionized compounds, retention on lAM columns and partitioning in 1 -octanol / water system were significantly different due to ionic interactions expressed in lAM retention but not in 1-octanol/water system and due to acidic and basic compounds behaving differently in these two systems. 

Finally the relation between log kjAM and partition in liposomes depends on analytes and was observed only for hydrophilic compounds [110]. 

A combination of the hydrophilic and hydrophobic parts of a molecule defines that molecule s amphiphilicity. A program has been described to calculate this property and calibrated against experimental values obtained from surface activity measurements [81]. It is possible that these values may be used to predict the effect on membranes leading to cytotoxicity or phospholipidosis, but they may also contain information (yet to be unraveled) on permeability. 

Immobilized artificial membranes (IAM) are another means of measuring lipophilic characteristics of drug candidates and other chemicals [90-94], IAM columns may better mimic membrane interactions than the isotropic octanol/water or other solvent/solvent partitioning system. These chromatographic indices appear to be a significant predictor of passive absorption through the rat intestine [95]. 

Immobilized liposome chromatography (ILC) is an (albeit related) alternative to IAM [96, 97]. Compounds with the same log P were shown to have very different degrees of membrane partitioning on ILC, depending on the charge of the compound [97]. 

Each of these scales produced a lipophilicity index that was related to - but not identical to - that obtained with octanol/water partitioning. 

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Ca can be complexed by crown ethers and cryptate ligands and ia this form can be transported across natural and artificial membranes. 

Fujikawa M, Ano R, Nakao K, Shimizu R and Akamatsu M. Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes application to prediction of Caco-2 cell permeability. Bioorg Med Chem 2005 13 4721-32. 

Artificial membrane systems can be prepared by appropriate techniques. These systems generally consist of mixtures of one or more phospholipids of natural or synthetic origin that can be treated (eg, by using mild sonication) to form spherical vesicles in which the lipids form a bilayer. Such vesicles, surrounded by a lipid bilayer, are termed liposomes. 

Some of the advantages and uses of artificial membrane systems in the study of membrane function can be briefly explained. 

The popular applications of the adsorption potential measurements are those dealing with the surface potential changes at the water/air and water/hydrocarbon interface when a monolayer film is formed by an adsorbed substance. " " " Phospholipid monolayers, for instance, formed at such interfaces have been extensively used to study the surface properties of the monolayers. These are expected to represent, to some extent, the surface properties of bilayers and biological as well as various artificial membranes. An interest in a number of applications of ordered thin organic films (e.g., Langmuir and Blodgett layers) dominated research on the insoluble monolayer during the past decade. 

When screening for absorption by passive membrane permeability, artificial membranes have the advantage of offering a highly reproducible and high-throughput system. Artificial membranes have been compared to Caco-2 cells and for passive... 

Camenisch, G., Folkers, G., Van de Waterbeemd, H. Comparison of passive drug transport through Caco-2 cells and artificial membranes. Int. J. Pharm. 1997, 147, 61-70. 

Faller, B., Grimm, H. P., Loeuillet-Ritzier, F., Arnold, S., Briand, X. High-throughput lipophilidty measurement with immobilized artificial membranes. J. Med. Chem. 2005, 48, 2571-2576. 

Reichel, A., Begley, D. J. Potential of immobilized artificial membranes for predicting drug penetration across the blood-brain barrier. Pharm. Res. 1998, 35,1270-1274. 

Kansy, M., Senner, F., Gubemator, K. Physicochemical high throughput screening parallel artificial membrane permeation assay in the description of passive absorption processes. /. Med. Chem. 1998, 43, 1007-1010. 

Sugano, K., Hamada, H., Machida, M., Ushio, H., Saitoh, K., Terada, K. Optimized conditions of bio-mimetic artificial membrane permeation assay. Int.J. Pharm. 2001, 228,181-188. 

PAMPA parallel artificial membrane permeation assay... 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

A., Barbato, E., Testa, B. Immobilized artificial membrane (lAM)-HPLC in drug research. /. Med. Chem. 2003, 46, 655-665. 

Pidgeon, C., Venkataram, U. V. Immobilized artificial membrane chromatography supports composed of membrane lipids. Anal. Eiochem. 1989,... 

Vrakas, D., Giaginis, C., Tsantili-Kakoulidou, A. Different retention behavior of structurally diverse basic and neutral drugs in immobilized artificial membrane and reversed-phase high performance liquid chromatography ... 

M., La Rotonda, M. L, Testa, B. Structural properties governing retention mechanisms on immobilized artificial membrane (lAM) HPLC columns. Helv. Chim. Acta 2002, 85, 519-532. 

Hollosy, F., Valko, K., Hersey, A., Nunhuck, S., Keri, G., Bevan, C. Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning. J. Med. Chem. 2006, 49, 6958-6971. 

Pauletti, G. M., Wunderli-Allenspach, H. Partition coefficients in vitro Artificial membranes as a standardized distribution model. Bur. J. Pharm. Sci. 1994, 1, 273-282. 

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