期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 105, 期 2, 页码 915-924出版社
WILEY
DOI: 10.1016/j.xphs.2015.11.035
关键词
intestinal absorption; membrane conductance and resistance; paracellular transport; permeability; tight junction; transcellular transport; ABC transporters; cell culture; intestinal epithelia
资金
- Grants-in-Aid for Scientific Research [15K18929] Funding Source: KAKEN
A human small intestinal epithelial cell (HIEC) monolayer was recently established in our laboratories as a novel system to evaluate the P-app (apparent permeability coefficient) of compounds during their absorption in humans. An effusion-based analysis using polyethylene glycol oligomers with molecular weights ranging from 194-898 indicated that HIEC and Caco-2 cell monolayers both had paracellular pores with 2 distinct radiuses (similar to 5 and 9-14 angstrom), whereas the porosity of large pores was 11-fold higher in the HIEC monolayer (44 x 10(-8)) than in the Caco-2 cells (4 x 10(-8)). A comparison between the fractionabsorbed (Fa) values observed in humans and those predicted from Papp values in both monolayers indicated that the HIEC monolayer had markedly higher precision to predict Fa values with root mean square error of 9.40 than the Caco-2 cells (root mean square error = 16.90) for 10 paracellularly absorbed compounds. Furthermore, the accuracy of the HIEC monolayer to classify the absorption of 23 test drugs with diverse absorption properties, including different pathways in the presence or absence of susceptibility to efflux transporters, was higher than that of the Caco-2 cell monolayer. In conclusion, the HIEC monolayer exhibited advantages over Caco-2 cells in the ranking and prediction of absorption of compounds in humans. (C) 2016 American Pharmacists Association r. Published by Elsevier Inc. All rights reserved.
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