Passive permeability tests

Let us take the exposure packages as an example technically, most of these assays are highly automated, require small amount of compounds and have a brief cycle time. Scientifically, they fulfill requirements to predict exposure by addressing the three major contributing factors solubility, passive permeability and metabolic (hepatic) clearance. These type of packages are ideal to explore or diagnose scaffold characteristics and define project flowcharts. They can be used repeatedly to test newly synthesized compounds and guide SAR. A number of compounds within a... 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

The kinetics of intestinal drug absorption, permeation enhancement, chemical moiety structure-permeability relationships, dissolution testing, in vitro/in vivo correlation, bioequivalence, and the development of novel polymeric materials are closely associated with the concept of Caco-2. As most drugs are known to absorb via intestines without using cellular pumps, passive permeability models... 

During the characterization process, hits are typically tested for kinetic solubility and permeability in a model of passive diffusion such as PAMPA [22]. As new compounds are synthesized, additional parameters also need to be considered, such as pZa, chemical and plasma stability, and protein binding. Calculated properties such as MW, clogP, and PSA should also be tracked. 

This refers to the transport across the epithelial cells, which can occur by passive diffusion, carrier-mediated transport, and/or endocytic processes (e.g., transcytosis). Traditionally, the transcellular route of nasal mucosa has been simply viewed as primarily crossing the lipoidal barrier, in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size. However, several investigators have reported the lack of linear correlation between penetrant lipophilicity and permeability [9], which implies that cell membranes of nasal epithelium cannot be regarded as a simple lipoidal barrier. Recently, compounds whose transport could not be fully explained by passive simple diffusion have been investigated to test if they could be utilized as specific substrates for various transporters which have been identified in the... 

Corrosion-inhibitive properties of the compound Na2P03F have been tested by Andrade et al., either by incorporating it in a mortar or as a penetrant[68]. This compound, which is currently available as a proprietary product, is reported to act as an anodic inhibitor, possibly with some cathodic action. The minimum required ratio of phosphate to chloride was suggested as 1 1. The mechanism of action of this admixture is to stabilize the passive layer of iron oxide on the steel and also increase the density of concrete, thus decreasing the permeability... 

The first step in this direction is to correlate the permeability values obtained in the Caco-2 cell lines (apical-basolateral direction, Pay) with the fraction of dose absorbed in vivo in rat For this proposal eight fluoroquinolones were assayed and the results found with Caco-2 cell lines were compared with those obtained in vivo in rat In the Caco-2 cell lines the permeability of the quinolones was evaluated at different initial concentration, in order to test for no linearities in the absorption process. For some of them, it was observed that a secretion system worked in the opposite direction to passive diffusion for this reason the permeability value used for the correlations, in the case of secretion, was the one obtained at the highest concentration of the quinolone, which corresponds to saturation of the secretion process. 

This is currently a hot topic in the EU, evident by the recent ban on the testing of cosmetic products on animals under the EU Cosmetics Directive [105]. In vitro cell cultures usually originate from a live animal so, ultimately, some animal sacrifice is necessary. Some synthetic systems do exist, such as serru-permeable membranes to model tissue passive transport. 

The parallel artificial membrane permeability assay (PAMPA) is a recent development in the area of artificial membranes that appears to offer considerable potential. Measuring the flux values (membrane permeation levels) of a range of test compounds by PAMPA and relating these values to the flux curves obtained in Caco-2 studies have shown good correlations, indicating that the PAMPA assay could be a good alternative to Caco-2 cells for the measurement of passively diffusing compounds. 

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