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Prediction of the Oral Absorption of Low-Permeability Drugs Using Small Intestine-Like 2/4/A1 Cell Monolayers

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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 Å, which is similar to that in the human small intestine, although the pore radius was smaller (3.7 ± 0.1 Å) 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.

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Authors and Affiliations

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

    Staffan Tavelin, Jan Taipalensuu, Lauri Söderberg & Per Artursson

  2. Center of Pharmaceutical Informatics, Sweden

    Staffan Tavelin

  3. Department of Metabolism & Pharmacokinetics, Bristol-Myers Squibb Co., Pharmaceutical Research Institute, Princeton, New Jersey, 08543

    Rick Morrison & Saeho Chong

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Correspondence to Per Artursson.

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Tavelin, S., Taipalensuu, J., Söderberg, L. et al. Prediction of the Oral Absorption of Low-Permeability Drugs Using Small Intestine-Like 2/4/A1 Cell Monolayers. Pharm Res 20, 397–405 (2003). https://doi.org/10.1023/A:1022699920043

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