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


CONCLUSIONS
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.
Tavelin
Staffan
S
Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden.
Taipalensuu
Jan
J
Söderberg
Lauri
L
Morrison
Rick
R
Chong
Saeho
S
Artursson
Per
P
D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats
D004364:Pharmaceutical Preparations