Evidence map›Paper›PMID 23801821›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2013

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, Mary F Paine

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.

0numbers the graph read from it
0cells of the map it votes in
24citing papers in PubMed
3.8field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

24 citing papers in PubMed, 42 citations in OpenAlex.

  1. Article
  2. Review
  3. Milk Thistle (Current medicinal chemistry · 2025
    Review
  4. Review
  5. Review
  6. Article
  7. Review
  8. Article
  9. Article
  10. Enzyme Activity of Natural Products on Cytochrome P450.Molecules (Basel, Switzerland) · 2022
    Review
  11. Review
  12. Review
  13. Review
  14. Review
  15. Review
  16. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.Drug metabolism and disposition: the biological fate of chemicals · 2016
    Review
  17. Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides.Drug metabolism and disposition: the biological fate of chemicals · 2015
    Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 2 institutions in 1 country.

Scott J BrantleyDivision of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Tyler N Graf
Nicholas H Oberlies
Mary F Paine
University of North Carolina at Chapel Hill · USUniversity of North Carolina at Greensboro · US

Funding

UNC Clinical and Translational Science AwardUL1TR000083 · NCATS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI RUNGE, MARSCHALL S. · 2012 to 2013
$11.6M
Mechanisms Underlying Drug-Diet InteractionsR01GM077482 · NIGMS · WASHINGTON STATE UNIVERSITY · PI PAINE, MARY F · 2007 to 2014
$3.3M
NCATS NIH HHS UL1 TR000083NCATS NIH HHS UL1TR000083NIGMS NIH HHS R01 GM077482NIGMS NIH HHS R01-GM077482
6 · The paper itself

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.

Indexed as

Cytochrome P-450 CYP3A InhibitorsCytochrome P-450 CYP3AEnzyme InhibitorsHerb-Drug InteractionsHumansInhibitory Concentration 50Intestinal MucosaIntestinesMicrosomes, LiverPlant ExtractsSilybum marianumCYP3A4 protein, humanCytochrome P-450 CYP3ACytochrome P-450 CYP3A InhibitorsEnzyme InhibitorsPlant Extracts

Identifiers

PMID23801821
PMCPMC3876807
OpenAlexW2142898360

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.