Evidence map›Paper›PMID 25253884›Full record

Trial reportThe Journal of pharmacology and experimental therapeutics2014

Assessment of a candidate marker constituent predictive of a dietary substance-drug interaction: case study with grapefruit juice and CYP3A4 drug substrates.

Garrett R Ainslie, Kristina K Wolf, Yingxin Li, Elizabeth A Connolly, Yolanda V Scarlett, J Heyward Hull, Mary F Paine

Open access · bronzeAbstract readClinical Trial, Phase IIRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The Journal of pharmacology and experimental therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.2field-weighted citation impact, top 19% 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

6 citing papers in PubMed, 14 citations in OpenAlex.

  1. Article
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  3. Review
  4. Review
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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

7 authors at 2 institutions in 1 country.

Garrett R AinslieCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
Kristina K WolfCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
Yingxin LiCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
Elizabeth A ConnollyCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
Yolanda V ScarlettCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
J Heyward HullCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.).
Mary F PaineCurriculum in Toxicology (G.R.A., M.F.P.) and Division of Gastroenterology and Hepatology (Y.V.S.), School of Medicine, and UNC Eshelman School of Pharmacy (K.K.W., Y.L., E.A.C., J.H.H.), The University of North Carolina, Chapel Hill, North Carolina; and Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (G.R.A., M.F.P.) mary.paine@wsu.edu.
University of North Carolina at Chapel Hill · USWashington State University Spokane · US

Funding

UNC CLINICAL AND TRANSLATIONAL SCIENCE AWARD: BPCAUL1RR025747 · NCRR · UNIV OF NORTH CAROLINA CHAPEL HILL · PI RUNGE, MARSCHALL S. · 2008 to 2011
$44.6M
TOXICOLOGYT32ES007126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ILONA JASPERS, Bernard E. Weissman · 1985 to 2026
$13.0M
Mechanisms Underlying Drug-Diet InteractionsR01GM077482 · NIGMS · WASHINGTON STATE UNIVERSITY · PI PAINE, MARY F · 2007 to 2014
$3.3M
NCRR NIH HHS UL1 RR025747NCRR NIH HHS UL1-RR025747NIEHS NIH HHS T32 ES007126NIEHS NIH HHS T32-ES007126NIGMS NIH HHS R01 GM077482NIGMS NIH HHS R01-GM077482PHS HHS UL1-R001111
6 · The paper itself

Abstract

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.

Indexed as

BeveragesCitrus paradisiAdultBiomarkersCross-Over StudiesCytochrome P-450 CYP3AFemaleFood-Drug InteractionsForecastingHumansLoperamideMaleMicrosomesMiddle AgedProspective StudiesSubstrate SpecificityBiomarkersCYP3A4 protein, humanCytochrome P-450 CYP3ALoperamide

Identifiers

PMID25253884
PMCPMC4244582
OpenAlexW2027243036

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.