Caco-2/TC7 cell line characterization for intestinal absorption: How reliable is this in vitro model for the prediction of the oral dose fraction absorbed in human?

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…Caco-2 cells are cultured on porous filter supports until fully differentiated and polarized, as denoted by a TEER in excess of 300 Ω cm 2 (van Breemen and Li, 2005), although lower values have also been reported (Buckley et al, 2012). Caco-2 TC7, a clone isolated from a late passage of the parental Caco-2 line, is as reliable a model for passive diffusion as the parental cell line; however it seems not to be predictable for intestinal absorption of highly lipophilic compounds and poorly absorbed compounds, or when transporter-mediated routes and/or first pass metabolism are involved (Turco et al, 2011). As the absorption of xenobiotics is not only restricted to passive diffusion, the expression of active transport and efflux systems (such as P-glycoprotein) in employed cell lines is certainly important (Yang, 2013).…”

“…A number of difficulties were encountered in such investigations: Caco-2 permeability values were not able to be obtained for 44% out of 32 tested chemicals due to poor or no detection, lack of stability, and/or lack of available analytical methods (Prieto et al, 2013). Several compounds (1,2-benzanthracene, phenantrene, hexa-, penta-and tetra-chlorobenzene) were excluded from the performed transport experiments due to their high lipophilicity, which created problems with respect to solubility and non-specific surface adsorption (Turco et al, 2011).…”

“…By knowing the differences between in vitro and in vivo, the performance of the cellular model could be improved by treating cells with known inducers/ inhibitors, or by using complementary in silico tools (Turco et al, 2011). The key parameters of a particular biobarrier model critical for each application setting also have to be established.…”

“…However, the models have not been properly evaluated for compounds with relatively poor absorption (e.g., below 30% within a short time period). Within the framework of the EU ACuteTox project, which aimed to develop a non-animal testing strategy to predict acute oral toxicity of chemicals in humans, the suitability of the Caco-2 cell line and the TC7 clone for prediction of intestinal transport of selected drugs and chemicals was investigated (Prieto et al, 2013;Turco interest in such models in each of the cosmetic/chemical, drug and food industries, it would be intriguing to conduct an analysis into why the state of the art, the choice (skin, intestine or lung) and the level of model implementation are rather different across these three industries.…”

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

“…The key processes that determine oral bioavailability (F oral ) of chemicals are generally described as i) the fraction that is absorbed into the enterocytes (f abs ), ii) model with good in vitro-in vivo correlations (Cascone et al, 2016). Figure 4A summarizes the results obtained from different studies, showing an empirical sigmoidal relationship against in vivo human absorption values with r 2 values ranging from 0.61 to 0.81 (Marino et al, 2005;Matsson et al, 2005;Miret et al, 2004;Turco et al, 2011). Current use of in vitro absorption methods shows that only Caco-2 absorption experiments are occasionally included in risk evaluations of food chemicals as well as medicines (Fig.…”