Evidence map›Paper›PMID 34074730›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2021

Quantitative Investigation of Irinotecan Metabolism, Transport, and Gut Microbiome Activation.

Md Masud Parvez, Abdul Basit, Parth B Jariwala, Zsuzsanna Gáborik, Emese Kis, Scott Heyward, Matthew R Redinbo, Bhagwat Prasad

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

Article in Drug metabolism and disposition: the biological fate of chemicals, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed
4.8field-weighted citation impact, top 4% 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

30 citing papers in PubMed, 69 citations in OpenAlex.

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  16. Experimental pharmacology in precision medicine.Pharmacology research & perspectives · 2023
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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

8 authors at 3 institutions in 2 countries.

Md Masud ParvezDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Abdul BasitDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Parth B JariwalaDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Zsuzsanna GáborikDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Emese KisDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Scott HeywardDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Matthew R RedinboDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.).
Bhagwat PrasadDepartment of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.M.P., A.B., B.P.); Departments of Chemistry, Biochemistry, and Microbiology, and the Integrated Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.B.J., M.R.R.); SOLVO Biotechnology, Budapest, Hungary (Z.G., E.K.); and BioIVT Inc., Baltimore, Maryland (S.H.) bhagwat.prasad@wsu.edu.
University of North Carolina at Chapel Hill · USWashington State University Spokane · USSolvo Biotechnology (Hungary) · HU

Funding

PBPK prediction of ontogeny mediated alteration in hepatic drug eliminationR01HD081299 · NICHD · WASHINGTON STATE UNIVERSITY · PI PRASAD, BHAGWAT · 2015 to 2025
$4.6M
Microbiome-Targeted Probes to Eliminate Chemotherapy-Induced GI ToxicityR01CA207416 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI REDINBO, MATTHEW R · 2016 to 2018
$1.7M
Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial EnzymesR01GM135218 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI REDINBO, MATTHEW R · 2019 to 2022
$1.5M
Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human HealthR01GM137286 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI REDINBO, MATTHEW R · 2020 to 2023
$1.2M
NCI NIH HHS R01 CA207416NICHD NIH HHS R01 HD081299NIGMS NIH HHS R01 GM135218NIGMS NIH HHS R01 GM137286
6 · The paper itself

Abstract

The anticancer drug irinotecan shows serious dose-limiting gastrointestinal toxicity regardless of intravenous dosing. Although enzymes and transporters involved in irinotecan disposition are known, quantitative contributions of these mechanisms in complex in vivo disposition of irinotecan are poorly understood. We explained intestinal disposition and toxicity of irinotecan by integrating 1) in vitro metabolism and transport data of irinotecan and its metabolites, 2) ex vivo gut microbial activation of the toxic metabolite SN-38, and 3) the tissue protein abundance data of enzymes and transporters relevant to irinotecan and its metabolites. Integration of in vitro kinetics data with the tissue enzyme and transporter abundance predicted that carboxylesterase (CES)-mediated hydrolysis of irinotecan is the rate-limiting process in the liver, where the toxic metabolite formed is rapidly deactivated by glucuronidation. In contrast, the poor SN-38 glucuronidation rate as compared with its efficient formation by CES2 in the enterocytes is the key mechanism of the intestinal accumulation of the toxic metabolite. The biliary efflux and organic anion transporting polypeptide-2B1-mediated enterocyte uptake can also synergize buildup of SN-38 in the enterocytes, whereas intestinal P-glycoprotein likely facilitates SN-38 detoxification in the enterocytes. The higher SN-38 concentration in the intestine can be further nourished by β-d-glucuronidases. Understanding the quantitative significance of the key metabolism and transport processes of irinotecan and its metabolites can be leveraged to alleviate its intestinal side effects. Further, the proteomics-informed quantitative approach to determine intracellular disposition can be extended to determine susceptibility of cancer cells over normal cells for precision irinotecan therapy. SIGNIFICANCE STATEMENT: This work provides a deeper insight into the quantitative relevance of irinotecan hydrolysis (activation), conjugation (deactivation), and deconjugation (reactivation) by human or gut microbial enzymes or transporters. The results of this study explain the characteristic intestinal exposure and toxicity of irinotecan. The quantitative tissue-specific in vitro to in vivo extrapolation approach presented in this study can be extended to cancer cells.

Indexed as

Hepatobiliary EliminationIrinotecanAntineoplastic AgentsCarboxylesteraseCell Line, TumorDose-Response Relationship, DrugEnzyme ActivationGastrointestinal MicrobiomeGlucuronidaseHumansInactivation, MetabolicLiverOrganic Anion TransportersTopoisomerase I InhibitorsAntineoplastic AgentsCarboxylesteraseGlucuronidaseIrinotecanOrganic Anion TransportersTopoisomerase I Inhibitors

Identifiers

PMID34074730
PMCPMC8407663
OpenAlexW3165095728

What OpenQuestion holds

Textmetadata
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Registered trials

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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.