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Research ArticleArticle

High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions

Guannan Li, Ke Huang, Dejan Nikolic and Richard B. van Breemen
Drug Metabolism and Disposition November 2015, 43 (11) 1670-1678; DOI: https://doi.org/10.1124/dmd.115.065987
Guannan Li
University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois
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Ke Huang
University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois
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Dejan Nikolic
University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois
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Richard B. van Breemen
University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois
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Abstract

Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry–based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography–tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example.

Footnotes

    • Received June 15, 2015.
    • Accepted August 17, 2015.
  • This work was supported by the National Institutes of Health Office of Dietary Supplements [Grant P50 AT000155] and the National Center for Complementary and Integrative Health [Grants P50 AT000155 and R01 AT007659].

  • dx.doi.org/10.1124/dmd.115.065987.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

CYP450 Cocktail Inhibition Assay Using UHPLC-MS/MS

Guannan Li, Ke Huang, Dejan Nikolic and Richard B. van Breemen
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1670-1678; DOI: https://doi.org/10.1124/dmd.115.065987

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Research ArticleArticle

CYP450 Cocktail Inhibition Assay Using UHPLC-MS/MS

Guannan Li, Ke Huang, Dejan Nikolic and Richard B. van Breemen
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1670-1678; DOI: https://doi.org/10.1124/dmd.115.065987
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