PT  - JOURNAL ARTICLE
AU  - Staffan Tavelin
AU  - Vladan Milovic
AU  - Göran Ocklind
AU  - Susanne Olsson
AU  - Per Artursson
TI  - A Conditionally Immortalized Epithelial Cell Line for Studies of Intestinal Drug Transport
DP  - 1999 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1212--1221
VI  - 290
IP  - 3
4099  - http://jpet.aspetjournals.org/content/290/3/1212.short
4100  - http://jpet.aspetjournals.org/content/290/3/1212.full
SO  - J Pharmacol Exp Ther1999 Sep 01; 290
AB  - A new cell culture model that better mimics the permeability of the human small intestine was developed for studies of passive drug transport. The intestinal epithelial cell line, 2/4/A1, conditionally immortalized with a temperature-sensitive mutant of the growth-promoting oncogene simian virus 40 (SV40) large T, was grown on permeable supports. The cells grew at 33°C, where the oncogene is fully active, but stopped growing and entered a differentiation program at 39°C, where the oncogene is inactive. Significant cell death was observed at 39°C and, therefore, growth conditions under which 2/4/A1 cells survive during the differentiation process were developed. Cells grown on extracellular matrices which contained laminin at an intermediate temperature of 37°C formed viable differentiated monolayers with tight junctions, an increased expression of brush border enzymes, and a paracellular permeability that was comparable to that of the human small intestine. The permeability of 17 structurally diverse drugs gave a sigmoidal relationship with the absorbed fraction of the drugs after oral administration to humans. The relationship was compared with those obtained with the well established Caco-2 model and after in vivo perfusion of the human jejunum. The transport of drugs with low permeability in 2/4/A1 monolayers was comparable to that in the human jejunum, and up to 300 times faster than that in Caco-2 monolayers. The transport of drugs with high permeability was comparable in all models. These results indicate that 2/4/A1 monolayers are promising alternatives to Caco-2 monolayers for studies of passive drug transport. The American Society for Pharmacology and Experimental Therapeutics