Permeability modeling

THE CASE FOR THE IDEAL IN VITRO ARTIFICIAL MEMBRANE PERMEABILITY MODEL... 

Since the widely accepted in vitro permeability model in the pharmaceutical industry is based on the use of cultured cells, such as Caco-2 or MDCK, it was appropriate to analyze the regression correlation coefficients based on the comparisons of Caco-2 log Pe and the log Pe values based on the human jejunal measurements [56]. 

The Ideal in vitro Artificial Membrane Permeability Model... 

Liang, E., K. Chessic, and M. Yazdanian. Evaluation of an accelerated Caco-2 cell permeability model, J. Pharm. Sci. 2000, 89, 336-345... 

M., Evaluation of an accelerated Caco-2 cell permeability model,... 

The VolSurf method was used to produce molecular descriptors, and PLS discriminant analysis (DA) was applied. The statistical model showed two significant latent variables after cross-validation. The 2D PLS score model offers a discrimination between the permeable and less permeable compounds. When the spectrum color is active (Fig. 17.2), red points refer to high permeability, whereas blue points indicate low permeability. There is a region in the central part of the plot with both red and blue compounds. In this region, and in between the two continuous lines, the permeability prediction is less reliable. The permeability model... 

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

While there are limitations associated with the use of an in vitro permeability model for assessing the transport of compounds across the buccal mucosa, it can still be useful in assessing and comparing the permeability of compounds under different conditions, such as pH, temperature, and osmolarity, which provide valuable information on the mechanisms involved in drug transport. Additionally, the preliminary effects of potential chemical penetration enhancers or formulation excipients may be assessed, and these may provide a substantial rationale for subsequently assessing the effect of these agents in man. 

Burns and Weaver [6] developed an MLR-based BBB permeability model using two experimental measures of BBB penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors based on Stein s hydrogen-bonding number and Randic s topological properties of the molecules. The final model accurately predicted the ability of test molecules to cross the BBB. 

Cell monolayers grown on permeable culture inserts form confluent mono-layers with barrier properties and can be used for drug absorption experiments. The most well-known cell line for the in vitro determination of intestinal drug permeability is the human colon adenocarcinoma Caco-2 [20, 21], The utility of the Caco-2 cell line is due to its spontaneous differentiation to enterocytes under conventional cell culture conditions upon reaching confluency on a porous membrane to resemble the intestinal epithelium. This cell model displays small intestinal carriers, brush borders, villous cell model, tight junctions, and high resistance [22], Caco-2 cells express active transport systems, brush border enzymes, and phase I and II enzymes [22-24], Permeability models... 

Although many laboratories have shown a correlation between their Caco-2 Papp data and Fabs in humans,35 39 the size of most data sets is too small to be able to derive useful permeability models. Thus, the possibility of pooling data from different sources to increase the size of the database used for modeling seems reasonable however, the success of this approach is highly unlikely considering the magnitude of the interlaboratory variability in Fapp values.40 The possibility of developing useful in silico models to predict absorption and permeability will remain limited unless databases of appropriate quality are developed. 

Sugano et al. studied the membrane permeation of 51 benzamidine-based thrombin inhibitors in a rat everted sac permeability model [197]. They reported significant membrane permeabilities in this in vitro model, which they attributed to passive paracellular transport, a different absorption mechanism to transcellular permeability. 

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