title: Application of a Human Intestinal Epithelial Cell Monolayer to the Prediction of Oral Drug Absorption in Humans as a Superior Alternative to the Caco-2 Cell Monolayer.
abstract: A human small intestinal epithelial cell (HIEC) monolayer was recently established in our laboratories as a novel system to evaluate the Papp (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 (∼ 5 and 9-14 Å), whereas the porosity of large pores was 11-fold higher in the HIEC monolayer (44 × 10(-8)) than in the Caco-2 cells (4 × 10(-8)). A comparison between the fraction-absorbed (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.
authors: Pharmacokinetics Research Laboratories, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan 300-2611.
authors: Toru
authors: T
authors: Takenaka
authors: Evaluation Research Laboratory, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan 300-2611.
authors: Naomoto
authors: N
authors: Harada
authors: Clinical & Research Quality Assurance, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan 771-0194.
authors: Jiro
authors: J
authors: Kuze
authors: Pharmacokinetics Research Laboratories, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan 300-2611.
authors: Masato
authors: M
authors: Chiba
authors: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan 467-8603.
authors: Takahiro
authors: T
authors: Iwao
authors: Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan 467-8603. Electronic address: tmatsu@phar.nagoya-cu.ac.jp.
authors: Tamihide
authors: T
authors: Matsunaga
mesh_terms: D000284:Administration, Oral; D018938:Caco-2 Cells; D005544:Forecasting; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations
keywords: ABC transporters; cell culture; intestinal absorption; intestinal epithelia; membrane conductance and resistance; paracellular transport; permeability; tight junction; transcellular transport