Evidence map›Paper›PMID 25008344›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2014

Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation.

Brandon T Gufford, Gang Chen, Philip Lazarus, 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, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
2.2field-weighted citation impact, top 12% 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

27 citing papers in PubMed, 44 citations in OpenAlex.

  1. Indinavir Increases MidazolamDrug metabolism and disposition: the biological fate of chemicals · 2019
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  12. The Chemistry of Kratom [Journal of natural products · 2020
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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

6 authors at 3 institutions in 1 country.

Brandon T GuffordSection of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.).
Gang ChenSection of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.).
Philip LazarusSection of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.).
Tyler N GrafSection of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.).
Nicholas H OberliesSection of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.).
Mary F PaineSection of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.) mary.paine@wsu.edu.
North Carolina Agricultural and Technical State University · USUniversity of North Carolina at Greensboro · USWashington State University Spokane · US

Funding

Mechanisms Underlying Drug-Diet InteractionsR01GM077482 · NIGMS · WASHINGTON STATE UNIVERSITY · PI PAINE, MARY F · 2007 to 2014
$3.3M
NIGMS NIH HHS R01 GM077482NIGMS NIH HHS R01-GM077482-S1
6 · The paper itself

Abstract

Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC(50) determination. The IC(50) values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC(50) determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clinical assessment.

Indexed as

BeveragesCell LineCitrus paradisiDietDrug InteractionsEnzyme InhibitorsGlucuronosyltransferaseHumansHymecromoneInhibitory Concentration 50Intestinal MucosaIntestinesMicrosomesSilybinSilymarinXenobioticsEnzyme InhibitorsGlucuronosyltransferaseHymecromoneSilybinSilymarinXenobiotics

Identifiers

PMID25008344
PMCPMC4164973
OpenAlexW2111034418

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.