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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Pharmacologic Targeting of Bacterial β-Glucuronidase Alleviates Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy in Mice

Amanda LoGuidice, Bret D. Wallace, Lauren Bendel, Matthew R. Redinbo and Urs A. Boelsterli
Journal of Pharmacology and Experimental Therapeutics May 2012, 341 (2) 447-454; DOI: https://doi.org/10.1124/jpet.111.191122
Amanda LoGuidice
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Bret D. Wallace
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Lauren Bendel
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Matthew R. Redinbo
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Urs A. Boelsterli
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Abstract

Small intestinal mucosal injury is a frequent adverse effect caused by nonsteroidal anti-inflammatory drugs (NSAIDs). The underlying mechanisms are not completely understood, but topical (luminal) effects have been implicated. Many carboxylic acid-containing NSAIDs, including diclofenac (DCF), are metabolized to acyl glucuronides (AGs), and/or ether glucuronides after ring hydroxylation, and exported into the biliary tree. In the gut, these conjugates are cleaved by bacterial β-glucuronidase, releasing the potentially harmful aglycone. We first confirmed that DCF-AG was an excellent substrate for purified Escherichia coli β-d-glucuronidase. Using a previously characterized novel bacteria-specific β-glucuronidase inhibitor (Inhibitor-1), we then found that the enzymatic hydrolysis of DCF-AG in vitro was inhibited concentration dependently (IC50 ∼164 nM). We next hypothesized that pharmacologic inhibition of bacterial β-glucuronidase would reduce exposure of enterocytes to the aglycone and, as a result, alleviate enteropathy. C57BL/6J mice were administered an ulcerogenic dose of DCF (60 mg/kg i.p.) with or without oral pretreatment with Inhibitor-1 (10 μg per mouse, b.i.d.). Whereas DCF alone caused the formation of numerous large ulcers in the distal parts of the small intestine and increased (2-fold) the intestinal permeability to fluorescein isothiocyanate-dextran, Inhibitor-1 cotreatment significantly alleviated mucosal injury and reduced all parameters of enteropathy. Pharmacokinetic profiling of DCF plasma levels in mice revealed that Inhibitor-1 coadministration did not significantly alter the Cmax, half-life, or area under the plasma concentration versus time curve of DCF. Thus, highly selective pharmacologic targeting of luminal bacterial β-d-glucuronidase by a novel class of small-molecule inhibitors protects against DCF-induced enteropathy without altering systemic drug exposure.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA98468] (to M.R.R.); the Boehringer Ingelheim Endowed Chair in Mechanistic Toxicology; a research grant from Helsinn Healthcare SA, Switzerland (to U.A.B.); the K. A. Nieforth Pharmacy Student Research Fund (to L.B.); and University of Connecticut School of Pharmacy Student Research Scholarship Fund (to L.B.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.191122.

  • ABBREVIATIONS:

    GI
    gastrointestinal
    DCF
    diclofenac
    DCF-AG
    diclofenac-1-β-O-acyl glucuronide
    FITC
    fluorescein isothiocyanate
    Inh-1
    Inhibitor-1 [1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]
    NSAID
    nonsteroidal anti-inflammatory drug
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    COX
    cyclooxygenase
    HPLC
    high-performance liquid chromatography
    NBT
    nitroblue tetrazolium
    AUC
    area under the plasma concentration versus time curve.

  • Received December 16, 2011.
  • Accepted February 9, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 2
1 May 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Bacterial β-Glucuronidase Inhibitor Eases NSAID Enteropathy

Amanda LoGuidice, Bret D. Wallace, Lauren Bendel, Matthew R. Redinbo and Urs A. Boelsterli
Journal of Pharmacology and Experimental Therapeutics May 1, 2012, 341 (2) 447-454; DOI: https://doi.org/10.1124/jpet.111.191122

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Bacterial β-Glucuronidase Inhibitor Eases NSAID Enteropathy

Amanda LoGuidice, Bret D. Wallace, Lauren Bendel, Matthew R. Redinbo and Urs A. Boelsterli
Journal of Pharmacology and Experimental Therapeutics May 1, 2012, 341 (2) 447-454; DOI: https://doi.org/10.1124/jpet.111.191122
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