Cryopreserved Human Intestinal Mucosal Epithelium: A Novel In Vitro Experimental System for the Evaluation of Enteric Drug Metabolism, Cytochrome P450 Induction, and Enterotoxicity

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Albert P LiQian Yang

Abstract

We report here a novel in vitro enteric experimental system, cryopreserved human intestinal mucosa (CHIM), for the evaluation of enteric drug metabolism, drug-drug interaction, drug toxicity, and pharmacology. CHIM was isolated from the small intestines of four human donors. The small intestines were first dissected into the duodenum, jejunum, and ileum, followed by collagenase digestion of the intestinal lumen. The isolated mucosa was gently homogenized to yield multiple cellular fragments, which were then cryopreserved in a programmable liquid cell freezer and stored in liquid nitrogen. After thawing and recovery, CHIM retained robust cytochrome P450 (P450) and non-P450 drug-metabolizing enzyme activities and demonstrated dose-dependent induction of transcription of CYP24A1 (approximately 300-fold) and CYP3A4 (approximately 3-fold) by vitamin D3 as well as induction of CYP3A4 (approximately 3-fold) by rifampin after 24 hours of treatment. Dose-dependent decreases in cell viability quantified by cellular ATP content were observed for naproxen and acetaminophen, with higher enterotoxicity observed for naproxen, consistent with that observed in humans in vivo. These results suggest that CHIM may be a useful in vitro experimental...Continue Reading

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Citations

Oct 20, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aarti Sawant-Basak, R Scott Obach
Dec 28, 2019·The Journal of Pharmacology and Experimental Therapeutics·A David Rodrigues, Andrew Rowland
Dec 28, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·A David RodriguesStefan Oswald
Nov 12, 2019·Journal of Biological Engineering·Jennifer E SpeerNancy L Allbritton
May 1, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Haeyoung ZhangBhagwat Prasad
Aug 31, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mari DaviesNenad Manevski
Jan 2, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kazuo TakayamaHiroyuki Mizuguchi
Dec 24, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·David M StresserSarah S Wilson
Feb 4, 2021·Pharmaceutics·Glenn LemmensPatrick Augustijns
May 14, 2021·Clinical and Translational Science·Hongbing WangShiew-Mei Huang
Sep 4, 2021·Pharmacology & Therapeutics·Christopher M ArianKenneth E Thummel
Oct 5, 2021·Clinical Pharmacology and Therapeutics·Ann-Cathrine Dalgård DunvaldTore B Stage

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