Surrogate membranes

In drug design one often uses an organic solvent as a surrogate for a cell membrane or for the blood-brain barrier in designing the partitioning... 

Due to the predicted and previously detected low concentrations of pesticides in environmental samples (usually around the nanogram per liter level), a preconcentration step of the water samples is necessary prior to measurement. In this way, a preconcentration factor of several orders of magnitude (200-1,000-fold) is mandatory to reach the low detection limits necessary for the identification of pesticides, especially in complex wastewater samples. Also, the use of surrogate standards (e.g., triphenyl phosphate) added before the extraction step is a common practice in order to account for possible errors during the extraction process and for quantitative purposes. The commonly used extraction methods for polar compounds from water matrices involve isolation using liquid-liquid extraction (LLE) and solid-phase extraction (SPE), which are commented on below. Other methods such as semipermeable membrane devices (SPMD) are also mentioned. 

Membrane-bound SCF supports the survival and proliferation of hematopoietic colony forming cells with a predominantly bi- or multipotent character, whereas soluble SI SCF promotes mainly the maintenance of unipotent precursors. Furthermore, the phenotype of CFC induced by membrane-bound SCF resembles that of cells supported by S1+MS5 stroma. Thus, membrane-bound SCF ectopically expressed in epithelial MMCE cells can function as a surrogate stroma system for CD34" cells. 

In order for a substance to be absorbed, it must cross biological membranes. Most substances cross by passive diffusion. This process requires a substance to be soluble both in lipid and water. The most useful parameters providing information on the potential for a substance to diffuse across biological membranes are the octanol/water partition coefficient (Log P) value and the water solubility. The Log value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol (used as a surrogate for lipid) and is a measure of lipophilicity. Log P values above zero indicate that the substance is more soluble in octanol than water, i.e., is lipophilic, and values below zero (negative values) indicate that the substance is more soluble in water than octanol, i.e., is hydrophilic. In general, moderate Log P values (between 0 and 4) are favorable for absorption. However, a substance with a Log P value around 0 and low water solubility (around 1 mg/1) will also be poorly soluble in lipids and hence not readily absorbed. It is therefore important to consider both the water solubility of a substance and its Log P value when assessing the potential of that substance to be absorbed. 

The octanol/water partition coefficient (log Poet) is used as a surrogate of the passive transcellular permeation. Ho vever, it has two drawbacks (i) low to moderate correlation with in vivo absorption (ii) time-consuming assay. Therefore, various artificial membrane assays were extensively investigated as alternative approaches with better predictive power and allowing for higher throughput. 

Recently, there is some negativity towards PAMPA [52], seemingly due to an overexpectation and misunderstanding of PAM PA and the science of passive membrane permeation [53]. PAMPA is a refined descendant of log Poet and is an improved surrogate measurement for passive transcellular permeation. PAMPA permeability usually correlates well with passive transcellular permeation. It is important to correctly understand the pros and cons of this tool and to use it appropriately in drug discovery. 

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]. 

TABLE 5.4 Rejection of Several Neutral Pharmaceuticals and Surrogates by the Polyamide (XLE) and the Cellulose Acetate (SC-3100) Membrane"... 

The problem of using octanol as a surrogate for membranes is even more pronounced when dealing with membrane-water partitioning of weak organic acids... 

Peptidomimetics have found wide application as biostable, bioavailable, and often potent surrogates of naturally occurring peptides. They form the basis of important families of enzyme inhibitors and they act as receptor agonists and antagonists. Peptide chemists are also gaining a deeper understanding of the structural features of this class of compounds that influence their ability to permeate biological membranes and their pharmacokinetic properties. 

Whole cell biosensors may be divided into two groups depending on whether or not it is necessary for the cellular membranes to be intact. If the cells are being used simply as a source of one or more bound enzymes then the integrity of the cellular membranes may be of little import whereas if the enzymes are not bound within the cells then the contiguity of the cellular membranes is of vital importance. The status of the cell membranes is of particular importance when it is necessary that the cells be alive (i.e., potentially or actually capable of cell division, etc.). This requirement imposes additional difficulties on the fabrication of devices. However, biosensors that contain intact whole cells have the potential to act as convenient surrogates for traditional applications of biological cells and systems. At the forefront are those applications... 

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