[Prediction of drug intestinal absorption and drug-induced intestinal toxicity with the use of human crypt-derived intestinal stem cells and their differentiated cells].

For the development of orally-administered drugs, quantitative prediction of drug intestinal absorption and drug-induced intestinal toxicity is one of the essential evaluation items. However, the current experimental systems have some critical problems such as large inter-species difference in animal studies and different gene expression levels between Caco-2 cells and human intact intestinal tissue. Thus, the construction of novel experimental systems which can reflect human intestinal physiology has been desired. We established stable 3D culture of intestinal stem cells in Matrigel originally isolated from surgical specimens and novel experimental systems for the prediction of intestinal absorption and toxicity with their differentiated cells. For the prediction of intestinal absorption, intestinal availability and PXR-mediated induction of pharmacokinetics-related genes could be predicted with our differentiated cells, but not Caco-2 cells due to the low expression levels of key molecules. For the prediction of intestinal toxicity, we evaluated the decrease in intracellular ATP level of intestinal stem cells by anticancer drugs to predict the risk of drug-induced severe diarrhea and serotonin release from EC (enterochromaffin) cell-rich spheroids to predict the risk of drug-induced emesis. Based on these in vitro assays, we succeeded in the prediction of the difference in the frequency of diarrhea and emesis in the clinical situation after administration of each tested drug. In this review, we summarized the major problems of current assays and usefulness of human crypt-derived intestinal stem cells and their differentiated cells for the prediction of clinical pharmacokinetics and toxicity of drugs in humans.