Evidence map›Paper›PMID 28450578›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2017

Integrated Assessment of Diclofenac Biotransformation, Pharmacokinetics, and Omics-Based Toxicity in a Three-Dimensional Human Liver-Immunocompetent Coculture System.

Ujjal Sarkar, Kodihalli C Ravindra, Emma Large, Carissa L Young, Dinelia Rivera-Burgos, Jiajie Yu, Murat Cirit, David J Hughes, John S Wishnok, Douglas A Lauffenburger and 2 more

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

Article in Drug metabolism and disposition: the biological fate of chemicals, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.

0numbers the graph read from it
0cells of the map it votes in
40citing papers in PubMed
9.1field-weighted citation impact, top 2% 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

40 citing papers in PubMed, 69 citations in OpenAlex.

  1. Article
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  5. HIVIL: A humanNAM journal · 2025
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  9. Modeling Tumor Cell Dormancy in an Ex Vivo Liver Metastatic Niche.Methods in molecular biology (Clifton, N.J.) · 2024
    Article
  10. Review
  11. Article
  12. Article
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  14. Review
  15. Review
  16. Article
  17. Article
  18. In Vitro Models for Studying Chronic Drug-Induced Liver Injury.International journal of molecular sciences · 2022
    Review
  19. Review
  20. Review
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

12 authors at 2 institutions in 2 countries.

Ujjal SarkarDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.) srt@mit.edu ujjal.sarkar@astrazeneca.com.
Kodihalli C RavindraDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Emma LargeDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Carissa L YoungDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Dinelia Rivera-BurgosDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Jiajie YuDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Murat CiritDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
David J HughesDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
John S WishnokDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Douglas A LauffenburgerDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Linda G GriffithDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.).
Steven R TannenbaumDepartments of Biological Engineering (U.S., K.C.R., C.L.Y., D.R.-B., J.Y., M.C., J.S.W., D.A.L., L.G.G., S.R.T.) and Chemistry (S.R.T.), Massachusetts Institute of Technology, Cambridge, Massachusetts; and CN Bio Innovations Ltd., Welwyn Garden City, Hertfordshire, United Kingdom (E.L., D.J.H.) srt@mit.edu ujjal.sarkar@astrazeneca.com.
CN Bio Innovations (United Kingdom) · GBMassachusetts Institute of Technology · US

Funding

TOXICOLOGY CORE UNITP30ES002109 · NIEHS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI LEVINE, STUART S · 1985 to 2020
$25.6M
NIEHS NIH HHS P30 ES002109
6 · The paper itself

Abstract

In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immunocompetent coculture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography-tandem mass spectrometry. DCF biotransformation was assessed after 48 hours of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans. Further characterization of secreted bile acids in the medium revealed that a glycine-conjugated bile acid was a sensitive marker of dose-dependent toxicity in this three-dimensional liver microphysiological system. Protein markers were significantly elevated in the culture medium at high micromolar doses of DCF, which were also observed previously for acute drug-induced toxicity in humans. In this immunocompetent model, lipopolysaccharide treatment evoked an inflammatory response that resulted in a marked increase in the overall number of acute phase proteins. Kupffer cell-mediated cytokine release recapitulated an in vivo proinflammatory response exemplified by a cohort of 11 cytokines that were differentially regulated after lipopolysaccharide induction, including interleukin (IL)-1

Indexed as

Anti-Inflammatory Agents, Non-SteroidalDiclofenacModels, BiologicalAcute-Phase ProteinsBiotransformationCoculture TechniquesCytokinesDose-Response Relationship, DrugHepatocytesHumansInflammationKupffer CellsLipopolysaccharidesLiverProtein BindingProteomicsAcute-Phase ProteinsAnti-Inflammatory Agents, Non-SteroidalCytokinesDiclofenacLipopolysaccharides

Identifiers

PMID28450578
PMCPMC5469400
OpenAlexW2608513314

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
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.