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

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

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. The cells were cultivated on permeable supports. The 2/4/ A1 expression of genes associated with tight junctions was compared w...

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Bibliographic Details
Published in:Pharmaceutical research Vol. 20; no. 3; pp. 397 - 405
Main Authors: TAVELIN, Staffan, TAIPALENSUU, Jan, SÖDERBERG, Lauri, MORRISON, Rick, SAEHO CHONG, ARTURSSON, Per
Format: Journal Article
Language:English
Published: New York, NY Springer 01-03-2003
Springer Nature B.V
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Biological Transport
Cell Line
Cell physiology
Fundamental and applied biological sciences. Psychology
General pharmacology
Humans
Intestinal Mucosa - cytology
Intestinal Mucosa - metabolism
Medical sciences
Membrane and intracellular transports
Molecular and cellular biology
Pharmaceutical Preparations - metabolism
Pharmaceutical technology. Pharmaceutical industry
Pharmacokinetics
Pharmacology. Drug treatments
Rats
Digestive system
Biological transport
Gut
Prediction
Oral administration
Cell junction
paracellular
Permeability
intestinal epithelia
In vitro
Absorption
Caco-2
Paracellular transport
Established cell line
Tight junction
drug absorption
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Summary: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. 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. 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. 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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ISSN:0724-8741
1573-904X
DOI:10.1023/a:1022699920043