Evidence map›Paper›PMID 25788542›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2015

Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis.

Mark J Canet, Matthew D Merrell, Rhiannon N Hardwick, Amy M Bataille, Sarah N Campion, Daniel W Ferreira, Stavra A Xanthakos, Jose E Manautou, H Hesham A-Kader, Robert P Erickson and 1 more

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In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.

0numbers the graph read from it
0cells of the map it votes in
31citing papers in PubMed
5.9field-weighted citation impact, top 3% 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

31 citing papers in PubMed, 68 citations in OpenAlex.

  1. Development of anFrontiers in pharmacology · 2025
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  10. Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier.Drug metabolism and disposition: the biological fate of chemicals · 2022
    Article
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  17. Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis.Toxicological sciences : an official journal of the Society of Toxicology · 2018
    Article
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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

11 authors at 4 institutions in 1 country.

Mark J CanetDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Matthew D MerrellDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Rhiannon N HardwickDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Amy M BatailleDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Sarah N CampionDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Daniel W FerreiraDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Stavra A XanthakosDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Jose E ManautouDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
H Hesham A-KaderDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Robert P EricksonDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
Nathan J CherringtonDepartments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.) cherrington@pharmacy.arizona.edu.
Pfizer (United States) · USCincinnati Children's Hospital Medical Center · USUniversity of Arizona · USUniversity of Connecticut · US

Funding

LCenter for Clinical and Translational Science and TrainingUL1TR001425 · NCATS · UNIVERSITY OF CINCINNATI · PI HEUBI, JAMES E., KISSELA, BRETT M · 2015 to 2024
$37.5M
SOUTHWEST ENVIRONMENTAL HEALTH SCIENCES CENTERP30ES006694 · NIEHS · UNIVERSITY OF ARIZONA · PI DEAN BILLHEIMER · 1994 to 2026
$36.7M
Training in Environmental Toxicology of Human DiseaseT32ES007091 · NIEHS · UNIVERSITY OF ARIZONA · PI Nathan J Cherrington · 1985 to 2026
$10.7M
Cincinnati Center for Clinical and Translational Sciences and TrainingUL1TR000077 · NCATS · UNIVERSITY OF CINCINNATI · PI HEUBI, JAMES E., TSEVAT, JOEL · 2012 to 2014
$9.9M
Pediatric Adverse Drug Reactions in NASHR01HD062489 · NICHD · UNIVERSITY OF ARIZONA · PI CHERRINGTON, NATHAN J · 2011 to 2015
$1.6M
Hepatoprotective Mrp3R01DK068039 · NIDDK · UNIVERSITY OF ARIZONA · PI CHERRINGTON, NATHAN J · 2005 to 2009
$1.5M
NCATS NIH HHS UL1 TR000077NCATS NIH HHS UL1 TR001425NICHD NIH HHS HD062489NICHD NIH HHS R01 HD062489NIDDK NIH HHS DK068039NIDDK NIH HHS R01 DK068039NIEHS NIH HHS ES006694NIEHS NIH HHS ES007091NIEHS NIH HHS P30 ES006694NIEHS NIH HHS T32 ES007091
6 · The paper itself

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

Indexed as

Up-RegulationAcetaminophenAdolescentAnalgesics, Non-NarcoticATP-Binding Cassette, Sub-Family C ProteinsBile CanaliculiBiotransformationChildCohort StudiesFatty LiverFemaleHumansLiverMaleMultidrug Resistance-Associated Protein 2Non-alcoholic Fatty Liver DiseaseABCC2 protein, humanAcetaminophenacetaminophen glucuronideacetaminophen sulfate esterAnalgesics, Non-NarcoticATP-Binding Cassette, Sub-Family C ProteinsMultidrug Resistance-Associated Protein 2multidrug resistance-associated protein 3

Identifiers

PMID25788542
PMCPMC4429682
OpenAlexW2078355729

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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.