Generation of Enterocyte-Like Cells with Pharmacokinetic Functions from XXXX Induced Pluripotent Stem Cells Using Small-Molecule Compounds.

@entity1 @entity5320 @entity4187 @entity4433 @entity5322 @entity37537 @entity540 @entity5060 @entity6900
UNASSIGNED: The small intestine plays an important role in all aspects of pharmacokinetics, but there is no system for the comprehensive evaluation of small-intestinal pharmacokinetics, including drug metabolism and absorption. In this study, we aimed to construct an intestinal pharmacokinetics evaluation system and to generate pharmacokinetically functional enterocytes from @entity1 induced pluripotent stem (iPS) cells. These cells were differentiated into intestinal stem cell-like cells using activin A and @entity540 . The resulting cells were differentiated into enterocytes in a medium containing epidermal growth factor and small-molecule compounds. The differentiated cells expressed intestinal marker genes and drug transporters. The expression of sucrase-isomaltase, an intestine-specific marker, was markedly increased by small-molecule compounds. The cells exhibited activities of drug-metabolizing enzymes expressed in enterocytes, including @entity4187 /2, @entity5060 , @entity4433 , @entity5320 , @entity5322 /5, @entity6900 , and SULT. Fluorescence-labeled dipeptide uptake into the cells was observed and was inhibited by ibuprofen, an inhibitor of the intestinal oligopeptide transporter @entity37537 / @entity37537 . @entity5322 mRNA expression level was increased by these compounds and induced by the addition of 1a,25-dihydroxyvitamin D3. @entity5322 /5 activity was also induced by 1a,25-dihydroxyvitamin D3 in cells differentiated in the presence of the compounds. All these results show that we have generated enterocyte-like cells having pharmacokinetic functions and identified small-molecule compounds that are effective for promoting intestinal differentiation and the gain of pharmacokinetic functions. Our enterocyte-like cells would be useful material for developing a novel evaluation system to predict @entity1 intestinal pharmacokinetics.
