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Research ArticleArticle

A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A Inhibitors

Scott J. Brantley, Tyler N. Graf, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition September 2013, 41 (9) 1662-1670; DOI: https://doi.org/10.1124/dmd.113.052563
Scott J. Brantley
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.J.B., M.F.P.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
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Tyler N. Graf
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.J.B., M.F.P.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
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Nicholas H. Oberlies
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.J.B., M.F.P.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
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Mary F. Paine
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (S.J.B., M.F.P.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
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Abstract

Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1′-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 μM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ∼60 and 90 μM, respectively, whereas those for the remaining constituents were >100 μM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI, ∼100 μM; kinact, ∼0.20 min−1) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.

Footnotes

    • Received April 18, 2012.
    • Accepted June 25, 2013.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM077482] and National Center for Research Resources and National Center for Advancing Translational Sciences [Grant UL1TR000083]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. WinNonlin software was generously provided to the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, by Certara as a member of the Pharsight Academic Center of Excellence Program.

  • This work was previously presented in part as a poster presentation: Brantley SJ, Graf TN, Oberlies NH, and Paine MF (2011) Identification of a single compound from the herbal supplement milk thistle as a candidate mechanism-based inhibitor of CYP3A activity. American Association of Pharmaceutical Scientists Annual Meeting and Exposition; 2011 Oct 23-27; Washington, DC.

  • dx.doi.org/10.1124/dmd.113.052563.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (9)
Drug Metabolism and Disposition
Vol. 41, Issue 9
1 Sep 2013
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Research ArticleArticle

Milk Thistle Flavonolignans Inhibit CYP3A Activity

Scott J. Brantley, Tyler N. Graf, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1662-1670; DOI: https://doi.org/10.1124/dmd.113.052563

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Research ArticleArticle

Milk Thistle Flavonolignans Inhibit CYP3A Activity

Scott J. Brantley, Tyler N. Graf, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1662-1670; DOI: https://doi.org/10.1124/dmd.113.052563
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