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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Application of Cryopreserved Human Intestinal Mucosa and Cryopreserved Human Enterocytes in the Evaluation of Herb-Drug Interactions: Evaluation of CYP3A Inhibitory Potential of Grapefruit Juice and Commercial Formulations of Twenty-Nine Herbal Supplements

Carol Loretz, Ming-Chih David Ho, Novera Alam, Walter Mitchell and Albert P. Li
Drug Metabolism and Disposition October 2020, 48 (10) 1084-1091; DOI: https://doi.org/10.1124/dmd.120.000033
Carol Loretz
In Vitro ADMET Laboratories Inc., Columbia, Maryland
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Ming-Chih David Ho
In Vitro ADMET Laboratories Inc., Columbia, Maryland
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Novera Alam
In Vitro ADMET Laboratories Inc., Columbia, Maryland
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Walter Mitchell
In Vitro ADMET Laboratories Inc., Columbia, Maryland
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Albert P. Li
In Vitro ADMET Laboratories Inc., Columbia, Maryland
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Abstract

Commercial formulations of 29 commonly used herbal supplements (HSs) and grapefruit juice were evaluated for drug interaction potential via quantification of their CYP3A inhibitory potential in two in vitro experimental models of human small intestine, cryopreserved human intestinal mucosa (CHIM), and cryopreserved human enterocytes (CHEs). Two CYP3A substrates were used—in the studies with CHIM, CYP3A activity was quantified via liquid chromatography tandem mass spectrometry quantification of midazolam 1’-hydroxylation, whereas in CHE, luciferin-IPA metabolism to luciferin was quantified by luminescence. Upon treatment of CHIM with the estimated lumen concentration of the HS upon each oral administration (manufacturers’ recommended dosage dissolved in 200 ml of culture medium), >80% CYP3A inhibition was observed for green tea extract, St. John’s wort, valerian root, horehound, and grapefruit juice. Less than 50% inhibition was observed for fenugreek, aloe vera, guarana, soy isoflavone, maca, echinacea, spirulina, evening primrose, milk thistle, cranberry, red yeast rice, rhodiola, ginkgo biloba, turmeric, curcumin, white kidney bean, garlic, cinnamon, saw palmetto berries, panax ginseng, black elderberry, wheat grass juice, flaxseed oil, black cohosh, and ginger root. The results were confirmed in a a dose-response study with HSs obtained from three suppliers for the four inhibitory HSs (green tea extract, horehound, St. John’s wort, valerian root) and three representative noninhibitory HSs (black cohosh, black elderberry, echinacea). Similar results were obtained with the inhibitory HSs in CHE. The results illustrate that CHIM and CHE represent physiologically relevant in vitro experimental models for the evaluation of drug interaction potential of herbal supplements. Based on the results, green tea extract, horehound, St. John’s wort, and valerian root may cause drug interactions with orally administered drugs that are CYP3A substrates, as was observed for grapefruit juice.

SIGNIFICANCE STATEMENT In vitro evaluation of 29 popular herbal supplements in cryopreserved human intestinal mucosa identified green tea extract, horehound, St. John’s wort, and valerian root to have CYP3A inhibitory potential similar to that for grapefruit juice, suggesting their potential to have clinically significant pharmacokinetic interaction with orally administered drugs that are CYP3A substrates. The results suggest that cryopreserved human intestinal mucosa can be used for in vitro evaluation of drug interactions involving enteric drug metabolism.

Footnotes

    • Received March 25, 2020.
    • Accepted July 10, 2020.
  • No external funding was received for the research described in this manuscript.

  • https://doi.org/10.1124/dmd.120.000033.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (10)
Drug Metabolism and Disposition
Vol. 48, Issue 10
1 Oct 2020
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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Enteric CYP3A Inhibitory Potential of Herbal Supplements

Carol Loretz, Ming-Chih David Ho, Novera Alam, Walter Mitchell and Albert P. Li
Drug Metabolism and Disposition October 1, 2020, 48 (10) 1084-1091; DOI: https://doi.org/10.1124/dmd.120.000033

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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Enteric CYP3A Inhibitory Potential of Herbal Supplements

Carol Loretz, Ming-Chih David Ho, Novera Alam, Walter Mitchell and Albert P. Li
Drug Metabolism and Disposition October 1, 2020, 48 (10) 1084-1091; DOI: https://doi.org/10.1124/dmd.120.000033
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