In vitro human cell-based experimental models for the evaluation of enteric metabolism and drug interaction potential of drugs and natural products.

Elements of key enteric drug metabolism and disposition pathways are reviewed to aid the assessment of the applicability of current cell-based enteric experimental systems for the evaluation of enteric metabolism and drug interaction potential. Enteric nuclear receptors include vitamin D receptor, constitutive androstane receptor, Pregnane X receptor, farnesoid X receptor, liver X receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor. Enteric drug metabolizing enzyme pathways include both P450 and non-P450 drug metabolizing enzymes based on gene expression, proteomics, and activity. Both uptake and efflux transporters are present in the small intestine, with P-glycoprotein found to be responsible for most drug-drug and food-drug interactions. The cell-based in vitro enteric systems reviewed are: 1. immortalized cell line model: the human colon adenocarcinoma (Caco-2) cells; 2. human stem cell-derived enterocyte models: stem cell enteric systems, either from intestinal crypt cells or induced pluripotent stem cells; and 3. primary cell models: human intestinal slices, cryopreserved human enterocytes, permeabilized cofactor-supplemented (MetMax{trade mark, serif}) cryopreserved human enterocytes, and cryopreserved human intestinal mucosa. The major deficiency with both immortalized cell lines and stem cell-derived enterocytes is that the activities of drug metabolizing enzymes, while detectable, are substantially lower than that for the intestinal mucosa in vivo. Human intestine slices, cryopreserved human enterocytes, MetMax{trade mark, serif} cryopreserved human enterocytes, and cryopreserved human intestinal mucosa retain robust enteric drug metabolizing enzyme activities and represent the most appropriate models for the evaluation of metabolism and drug interaction potential of orally administered xenobiotics including drugs, botanical products, and dietary supplements. Significance Statement The current in vitro human cell-based enteric experimental systems are reviewed for applications toward the evaluation of the metabolism and drug interaction potential of orally administered substances. Due to the robust drug metabolizing enzyme activities, human intestinal slices, cryopreserved human enterocytes and cryopreserved human intestinal mucosa are concluded to represent appropriate experimental models for this application.