Screening for Intestinal Permeability

MTX have also been evaluated as models with modified paracellular permeability and the additional presence of a mucus layer [77, 79, 81], 

Another human colonic cancer cell line is T84 this develops monolayers of high TER ( 1000 Q cm2) when grown on permeable supports, but cells are not well differentiated and have been described as resembling a colonic crypt cell phenotype. Hence, these cells have been used mainly in studies of epithelial ion transport and are generally not considered to be adequate for drug transport studies, particularly with respect to carrier-mediated processes [10, 79, 82-84]. 

The rat intestinal cell line IEC-18 has been evaluated as a model to study small intestinal epithelial permeability. This cell line forms very leaky monolayers with TER of 50 n cm2 and permeability to mannitol of 8 x 10-6 cm s 1. The IEC-18 model was proposed to be a better model than the Caco-2 monolayers for evaluating the small intestinal paracellular permeation of hydrophilic molecules. However, the leakier paracellular pathway is related to the poor differentiation level of the cells and an undeveloped paracellular barrier lacking peri-junctional actin-belt. In addition, due to the poor differentiation the cells have minute expression of transporters and are therefore not useful for studies of carrier-mediated transport [82, 84] 

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Caco-2 monolayer, a model for human intestinal permeability, is commonly used in drug discovery to screen discovery compounds.34,35 The method involves measurement of flux of... 

One of the major obstacles to definitively examining the role of formulation components on enterocyte-based processes is the possible effect of excipient inclusion on other complicating factors. For example, the inclusion of lipids or surfactants in in vitro metabolic or transport screens runs the risk of affecting the thermodynamic activity of the drug in solution, thereby obscuring the role of metabolic and transport processes. Similarly, some surfactants and lipid-surfactant conjugates may cause transient increases in intestinal permeability as... 

More than a decade ago, Caco-2 cells grown on permeable supports were introduced as an experimental tool for mechanistic studies of intestinal drug transport [1-4]. At the same time it was suggested that the Caco-2 model was suitable for screening intestinal drug permeability and predicting the oral absorption potential... 

Several attempts have been made to estimate the dose required in humans in relation to a drug s potency, and to put this into the context of solubility and permeability for an optimal oral drug [2, 3]. A relatively simple example of this is where a 1.0 mg kg-1 dose is required in humans, then 52 pg mL"1 solubility is needed if the permeability is intermediate (20-80%) [3]. This solubility corresponds approximately to 100 pM of a compound with a MW of 400 g mol-1. Most screening activities for permeability determinations in, e.g., Caco-2, are made at a concentration of 10 pM or lower due to solubility restrictions. The first implication of this is that the required potency for these compounds needs to correspond to a dose of <0.1 mg kg-1 in humans if the drug should be considered orally active. Another implication would be the influence of carrier-mediated transport (uptake or efflux), which is more evident at low concentrations. This could result in low permeability coefficients for compounds interacting with efflux transporters at the intestinal membrane and which could either be saturated or of no clinical relevance at higher concentrations or doses. 

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