Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity
Yusuke Kamiya, Hiroka Takaku, Rio Yamada, Chisato Akase, Yuto Abe, Yuko Sekiguchi, Norie Murayama, Makiko Shimizu, Masato Kitajima, Fumiaki Shono, Kimito Funatsu, Hiroshi Yamazaki
Abstract
Apparent permeability coefficients (Papp) across a human intestinal epithelial Caco-2 cell monolayer were measured for a range of industrial/drug chemicals. A predictive equation for determining in vitro Papp values of fifty-six substances was set up using multivariate regression analysis based on in silico-estimated physicochemical properties (molecular weights and water distribution coefficients for apical and basal pH environments) (r = 0.77, p < 0.01). Predicted logPapp values of a secondary set of 34 compounds were correlated with the measured values. Under the medicinal logPapp values associated with their reported fraction absorbed, a significant inverse non-linear correlation was found between the logarithmic transformed values of observed Papp values and reported hepatic no-observed-effect levels of industrial chemicals (r = –0.55, p < 0.01, n = 29). In vitro determination and/or in silico prediction of permeability across intestinal cells could be effective for estimating oral absorption as a putative indicator for hepatotoxicity.