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Pharm Res. 2003 Mar;20(3):397-405.

Prediction of the oral absorption of low-permeability drugs using small intestine-like 2/4/A1 cell monolayers.

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  • 1Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden.

Abstract

PURPOSE:

To characterize the paracellular route of 2/4/A1 monolayers and to compare the permeabilities of incompletely absorbed oral drugs in 2/4/A1 with those in Caco-2 monolayers.

METHODS:

The cells were cultivated on permeable supports. The 2/4/ A1 expression of genes associated with tight junctions was compared with that in the small intestine using RT-PCR. The aqueous pore radii were determined using paracellular marker molecules. The permeabilities of a series of incompletely absorbed drugs (defined as having a fraction absorbed 0 to 80%) after oral administration to humans were studied.

RESULTS:

Occludin and claudin 1 and 3 were expressed in 2/4/A1. The pore radius of 2/4/A1 was 9.0 +/- 0.2 A. which is similar to that in the human small intestine, although the pore radius was smaller (3.7 +/- 0.1 A) in Caco-2. The relationship between permeability and fraction absorbed of 13 drugs was stronger in 2/4/A1 than in Caco-2. The relationships were used to predict the intestinal absorption of another seven drugs. The prediction was more accurate in 2/4/A1 (RMSE = 15.6%) than in Caco-2 (RMSE = 21.1%). Further, Spearman's rank coefficient between FA and permeability was higher in 2/4/A1.

CONCLUSION:

The improved 2/4/A1 cell culture model has a more in vivo-like permeability and predicted the oral absorption of incompletely absorbed drugs better than Caco-2 cells.

PMID:
12669959
[PubMed - indexed for MEDLINE]
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