In vitro experimental system for the evaluation of intestinal drug metabolism, drug‐drug interactions, and drug toxicity

The small intestines play an important role in the fates and biological effects of orally administered drug. Primary enterocyte isolates retaining in vivo drug metabolizing enzyme activities represent an ideal system for the evaluation of enteric drug properties, akin to the use of primary hepatocytes for the evaluation of hepatic drug properties. In our laboratory, we have developed three in vitro enteric experimental system from primary enteric isolates of the human intestines: cryopreserved enterocytes; permeabilized cryopreserved enterocytes (MetMax cryopreserved enterocytes), and cryopreserved intestinal mucosa. All three systems retain in vivo P450 and non-P450 drug metabolizing enzyme activities, including CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4, CYPJ2, CES2, UGT and SULT. The MetMax cryopreserved enterocytes represent a convenient model of the cryopreserved enterocytes, allowing storage at − 80 deg. C rather than liquid nitrogen, and use upon thawing without a need for centrifugation and cell viability determination. Cryopreserved intestinal mucosa represent the most complete in vitro model of the small intestinal epithelium, with all cell types represented with retention of cell-cell junctions as present in the organ in vivo. All three systems can be used for the evaluation of enteric drug metabolism and inhibitory drug-drug interactions, while cryopreserved enterocytes and cryopreserved intestinal mucosa can also be used for enterotoxicity studies. Cryopreserved intestinal mucosa can also be used for P450 induction studies, as demonstrated by the induction of CYP3A4 by rifampin and the induction of CYP24A1 and CYP3A4 by vitamin D3. The in vitro enteric experimental systems described above are readily applicable in drug development to aid the selection of drug candidates with the most appropriate human enteric drug properties. Support or Funding Information None Preparation of Cryopreserved Human Intestinal Mucosa Preparation of Cryopreserved Human Intestinal Mucosa This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.