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Abstract

In vitro and in situ experimental models that are descriptive of drug absorption in vivo are valuable tools in the discovery of new chemical entities that are bioavailable after oral administration. The specific objective of the study was to compare the intestinal permeabilities obtained in the three absorption models for consistency, and to assess the utility of the models in predicting the fraction of dose absorbed in human studies. The intestinal absorption models that were compared are widely used: the rat in situ single-pass intestinal perfusion system, the rat everted intestinal ring method, and monolayers of human colon adenocarcinoma cell line (CACO-2). The models were compared using small molecular reference compounds, as well as a series of peptidomimetic (PM) analogs. Each model had strong potential for estimating the fraction absorbed. For small organic molecules, excellent correlation was observed when permeabilities from CACO-2 cells and perfusions, or everted rings and perfusions, were compared. Weaker correlation was observed between everted rings and CACO-2 cells. Permeabilities for the set of reference compounds and PMs were positively correlated between any two of the three systems. Variance between correlations for reference compounds and PMs are likely due to structural features and physicochemical properties that are unique to the latter class of compounds. The results support caution in extrapolating correlations based on findings with small organic molecules to the behavior of complex peptidomimetics. Corroboration of permeabilities with two methods of determination is a useful cross-validation of experimental systems, as well as producing a reliable permeability assessment.(ABSTRACT TRUNCATED AT 250 WORDS)

Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency, proteolytic stability and transmembrane passage in vitro

“…Despite this, relating P app in this assay for a given compound to its likely in vivo absorption remains a difficult prospect. Several groups [29][30][31][32] have reported very strong individual correlations between P app across Caco-2 monolayers and in vivo absorption across intestinal epithelium in vivo. However, as noted by Artursson and colleagues 33 the correlation between studies is poor.…”

Membrane Transport of Drugs in Different Regions of the Intestinal Tract of the Rat

“…[4][5][6][7][8][9][10] The ability to penetrate the epithelial barrier, i.e., permeability, has been shown to correlate between data obtained in different animal models and the fraction absorbed in vivo in humans. 4,5,11,12 Direct comparisons of the effective permeability coefficients obtained in Caco-2-cell monolayers, in in situ rat perfusion, and excised segments in the Ussing chamber with the human jejunal permeability have also recently been reported. 8,13,14 These model correlations have been useful in order to evaluate possibilities and limitations regarding both passive and carrier-mediated transport mechanisms.…”

HT29-MTX/Caco-2 Cocultures as an in Vitro Model for the Intestinal Epithelium: In Vitro–in Vivo Correlation with Permeability Data from Rats and Humans

“…[1][2][3][4][5][6] The experimental models are designed to isolate the barrier of interest to permit relatively rapid and mechanistic evaluation of drug candidates. The Caco-2 cell line, a well-differentiated human intestinal cell line, has been investigated as a potential in vitro model for oral drug absorption and metabolism studies.…”