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
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DOI：
10.1023/a:1022699920043
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发表时间：
2003-03-01
影响因子：
3.7
通讯作者：
Artursson, P
中科院分区：
文献类型：
--
作者：
Tavelin, S;Taipalensuu, J;Artursson, P
目的。研究2/4/A1单层的细胞旁途径，比较2/4/A1和Caco-2单层中未完全吸收的口服药物的通透性。细胞培养在可渗透的载体上。用RT-PCR方法比较紧密连接相关基因2/4/A1在小肠组织中的表达。用细胞旁标记分子测定房水微孔半径。研究了人体口服一系列不完全吸收药物(定义为吸收程度为0~80%)的渗透性。2/4/A1表达occludin和claudin 1、3。2/4/A1的孔半径为9.0+/-0.2埃，与人的小肠相似，但CaCO-2的孔半径较小(3.7+/-0.1埃)。在2/4/A1中，13种药物的渗透性与吸收分数的关系比在CaCO-2中更强。这些关系被用来预测另外七种药物的肠道吸收。2/4/A1的预测准确率(RMSE=15.6%)高于Caco-2(RMSE=21.1%)。此外，FA与通透性之间的Spearman等级系数在2/4/A1中较高。改进的2/4/A1细胞培养模型具有更接近体内的渗透性，并比Caco-2细胞更好地预测未完全吸收的药物的口服吸收。
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 Angstrom, which is similar to that in the human small intestine, although the pore radius was smaller (3.7 +/- 0.1 Angstrom) 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.