02477nas a2200385   4500000000100000000000100001008004100002260001500043653001900058653001800077100001800095700002500113700001900138700001500157700002000172700001600192700001800208700001500226700001900241700001700260700002100277700002200298700002100320700001500341700002000356700001500376700002200391700001500413245012000428856005500548300001000603490000700613520145700620022001402077       2024                            d  c2024-12-0210aDrug Discovery10aPharmaceutics1 aTomoki Imaoka1 aReiko Onuki-Nagasaki1 aHiroshi Kimura1 aKempei Tai1 aMitsuharu Ishii1 aAyaka Nozue1 aIkuko Kaisaki1 aMisa Hoshi1 aKengo Watanabe1 aKazuya Maeda1 aTakashi Kamizono1 aTakahiro Yoshioka1 aTakashi Fujimoto1 aTaku Satoh1 aHiroko Nakamura1 aOsamu Ando1 aHiroyuki Kusuhara1 aYuzuru Ito00aDevelopment of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut  uhttps://www.nature.com/articles/s41598-024-80946-6  a299210 v143 aThere is an urgent need for novel methods that can accurately predict intestinal absorption of orally administered drugs in humans. This study aimed to evaluate the potential of a novel gut microphysiological system (MPS), gut MPS/Fluid3D-X, to assess the intestinal absorption of drugs in humans. The gut MPS/Fluid3D-X model was constructed using a newly developed flow-controllable and dimethylpolysiloxane-free MPS device (Fluid3D-X®). Human induced pluripotent stem cells-derived small intestinal epithelial cells were employed in this model, which exhibited key characteristics of the human absorptive epithelial cells of the small intestine, including the expression of key gene transcripts responsible for drug transport and metabolism, and the presence of dome-like protrusions in the primary intestinal epithelium under air-liquid interface culture conditions. Functional studies of transporters in the constructed model demonstrated basal-to-apical directional transport of sulfasalazine and quinidine, substrates of the active efflux transporters breast cancer resistance protein and P-glycoprotein, respectively, which were diminished by inhibitors. Furthermore, a cytochrome P450 (CYP) 3A inhibitor increased the apical-to-basal transport of midazolam, a typical CYP3A4 substrate, and reduced metabolite formation. These results suggest that gut MPS/Fluid3D-X has the potential to assess the intestinal absorption of small-molecule drugs.  a2045-2322