@article {KitaguchiDMD-AR-2021-000605, author = {Takashi Kitaguchi and Taisei Mizota and Mina Ito and Katsutoshi Ohno and Kazuhiro Kobayashi and Isamu Ogawa and Shimeng Qiu and Takahiro Iwao and Nobumitsu Hanioka and Mitsuru Tanaka and Tamihide Matsunaga}, title = {Simultaneous evaluation of membrane permeability and UDP-glucuronosyltransferase-mediated metabolism of food-derived compounds using human induced pluripotent stem cell-derived small intestinal epithelial cells}, elocation-id = {DMD-AR-2021-000605}, year = {2021}, doi = {10.1124/dmd.121.000605}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Pharmacokinetic prediction after oral ingestion is important for quantitative risk assessment of food-derived compounds. To evaluate the utility of human intestinal absorption prediction, we compared the membrane permeability and metabolic activities of human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIECs) with Caco-2 cells or human primary enterocytes (hPECs). We found that membrane permeability in hiPSC-SIECs had better predictivity than that in Caco-2 cells against 21 drugs with known human intestinal availability (r = 0.830 and 0.401, respectively). Membrane permeability in hiPSC-SIECs was only 0.019-0.25-fold as compared with that in Caco-2 cells for 7 in 15 food-derived compounds, primarily those which were reported to undergo glucuronidation metabolism. The metabolic rates of the glucuronide conjugate were similar or higher in hiPSC-SIECs as compared with hPECs, while lower in Caco-2 cells. Expression levels of UDP-glucuronosyltransferase (UGT) isoform mRNA in hiPSC-SIECs were similar or higher as compared with hPECs. Therefore, hiPSC-SIECs could be a useful tool for predicting human intestinal absorption, in order to simultaneously evaluate membrane permeability and UGT-mediated metabolism. Significance Statement Gastrointestinal absorption is an important step for predicting the internal exposure of food-derived compounds. This research revealed that human induced pluripotent stem cell-derived small intestinal cells (hiPSC-SIECs) had better predictivity of intestinal availability than Caco-2 cells; furthermore, the metabolic rates of UGT substrates of hiPSC-SIECs were closer those of human primary enterocytes than those of Caco-2 cells. Therefore, hiPSC-SIECs could be a useful tool for predicting human intestinal absorption to simultaneously evaluate membrane permeability and UGT-mediated metabolism.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2021/10/20/dmd.121.000605}, eprint = {https://dmd.aspetjournals.org/content/early/2021/10/20/dmd.121.000605.full.pdf}, journal = {Drug Metabolism and Disposition} }