Application of Intestinal Epithelial Cells Differentiated from Human Induced Pluripotent Stem Cells for Studies of Prodrug Hydrolysis and Drug Absorption in the Small Intestine

• DOI: 10.1124/dmd.118.083246
• Publication Date: 2018-08-22T16:25:24Z
• Authors: Takanori Akazawa; Shinpei Yoshida; Shuichi Ohnishi; Takushi Kanazu; Makoto Kawai; Koji Takahashi
• Keywords: Abcg2; Fexofenadine; Paracellular transport

Cell models to investigate intestinal absorption functions, such as those of transporters and metabolic enzymes, are essential for oral drug discovery development. The purpose this study was generate epithelial cells from human induced pluripotent stem (hiPSC-IECs) then clarify whether the functions hydrolase in them reflect small intestine. hiPSC-IECs showed transport activities P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), peptide transporter 1 (PEPT1), revealed by using their probe substrates ([3H]digoxin, sulfasalazine, [14C]glycylsarcosine), CYP3A4, CES2, CES1, which were clarified (midazolam, irinotecan, temocapril). intrinsic clearance hydrolysis six ester prodrugs into active form correlated with plasma exposure (Cmax , AUC, bioavailability) after administration these rats. Also, permeability coefficients 14 drugs, containing two P-gp (doxorubicin [3H]digoxin), one substrate BCRP (sulfasalazine), 11 nonsubstrates (ganciclovir, [14C]mannitol, famotidine, sulpiride, atenolol, furosemide, ranitidine, hydrochlorothiazide, acetaminophen, propranolol, antipyrine) values fraction (Fa) clinical studies. These findings suggest that would be a useful cell model predict