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Research ArticleSpecial Section – New Models in Drug Metabolism and Transport

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

Albert P. Li, Novera Alam, Kirsten Amaral, Ming-Chih David Ho, Carol Loretz, Walter Mitchell and Qian Yang
Drug Metabolism and Disposition November 2018, 46 (11) 1562-1571; DOI: https://doi.org/10.1124/dmd.118.082875
Albert P. Li
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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Novera Alam
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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Kirsten Amaral
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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Ming-Chih David Ho
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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Carol Loretz
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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Walter Mitchell
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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Qian Yang
In Vitro ADMET Laboratories Inc., Advanced Pharmaceutical Sciences Inc., Columbia, Maryland
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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 model for the evaluation of enteric drug properties, including drug metabolism, drug-drug interactions, and drug toxicity.

Footnotes

    • Received June 2, 2018.
    • Accepted July 11, 2018.
  • https://doi.org/10.1124/dmd.118.082875.

  • Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 46 (11)
Drug Metabolism and Disposition
Vol. 46, Issue 11
1 Nov 2018
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Research ArticleSpecial Section – New Models in Drug Metabolism and Transport

Cryopreserved Human Intestinal Mucosa

Albert P. Li, Novera Alam, Kirsten Amaral, Ming-Chih David Ho, Carol Loretz, Walter Mitchell and Qian Yang
Drug Metabolism and Disposition November 1, 2018, 46 (11) 1562-1571; DOI: https://doi.org/10.1124/dmd.118.082875

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Research ArticleSpecial Section – New Models in Drug Metabolism and Transport

Cryopreserved Human Intestinal Mucosa

Albert P. Li, Novera Alam, Kirsten Amaral, Ming-Chih David Ho, Carol Loretz, Walter Mitchell and Qian Yang
Drug Metabolism and Disposition November 1, 2018, 46 (11) 1562-1571; DOI: https://doi.org/10.1124/dmd.118.082875
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