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Research ArticleArticle

In Vitro Glucuronidation of the Antibacterial Triclocarban and Its Oxidative Metabolites

N. H. Schebb, B. Franze, R. Maul, A. Ranganathan and B. D. Hammock
Drug Metabolism and Disposition January 2012, 40 (1) 25-31; DOI: https://doi.org/10.1124/dmd.111.042283
N. H. Schebb
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B. Franze
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R. Maul
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A. Ranganathan
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B. D. Hammock
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Abstract

Triclocarban (3,4,4′-trichlorocarbanilide; TCC) is widely used as an antibacterial in bar soaps. During use of these soaps, a significant portion of TCC is absorbed by humans. For the elimination from the body, glucuronidation plays a key role in both biliary and renal clearance. To investigate this metabolic pathway, we performed microsomal incubations of TCC and its hydroxylated metabolites 2′-OH-TCC, 3′-OH-TCC, and 6-OH-TCC. Using a new liquid chromatography-UV-mass spectrometry method, we could show a rapid glucuronidation for all OH-TCCs by the uridine-5′-diphosphate-glucuronosyltransferases (UGT) present in liver microsomes of humans (HLM), cynomolgus monkeys (CLM), rats (RLM), and mice (MLM). Among the tested human UGT isoforms, UGT1A7, UGT1A8, and UGT1A9 showed the highest activity for the conjugation of hydroxylated TCC metabolites followed by UGT1A1, UGT1A3, and UGT1A10. Due to this broad pattern of active UGTs, OH-TCCs can be efficiently glucuronidated in various tissues, as shown for microsomes from human kidney (HKM) and intestine (HIM). The major renal metabolites in humans, TCC-N-glucuronide and TCC-N′-glucuronide, were formed at very low conversion rates (<1%) by microsomal incubations. Low amounts of N-glucuronides were generated by HLM, HIM, and HKM, as well as by MLM and CLM, but not by RLM, according to the observed species specificity of this metabolic pathway. Among the human UGT isoforms, only UGT1A9 had activity for the N-glucuronidation of TCC. These results present an anomaly where in vivo the predominant urinary metabolites of TCC are N and N′-glucuronides, but these compounds are slowly produced in vitro.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants P42-ES04699, R01-ES002710] through the German Academic Exchange Service (DAAD, Bonn, Germany); and the American Asthma Foundation (to B.D.H.).

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

    http://dx.doi.org/10.1124/dmd.111.042283.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    TCC
    3,4,4′-trichlorocarbanilide
    ACN
    acetonitrile
    CLM
    cynomolgus monkey liver microsomes
    I.S.
    internal standards
    DCC
    4,4′-dichlorcarbanilide
    DMSO
    dimethyl sulfoxide
    ESI
    electrospray ionization
    MS/MS
    tandem mass spectrometry
    MS
    mass spectrometry
    LC
    liquid chromatography
    HLM
    human liver microsomes
    HKM
    human kidney microsomes
    HIM
    human intestine microsomes
    MLM
    mice liver microsomes
    RLM
    rat liver microsomes
    SRM
    selected reaction monitoring
    UDPGA
    UDP-diphosphoglucuronic acid
    UGT
    uridine-5′-diphosphate-glucuronosyltransferases.

  • Received August 10, 2011.
  • Accepted September 27, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

GLUCURONIDATION OF TCC AND ITS METABOLITES

N. H. Schebb, B. Franze, R. Maul, A. Ranganathan and B. D. Hammock
Drug Metabolism and Disposition January 1, 2012, 40 (1) 25-31; DOI: https://doi.org/10.1124/dmd.111.042283

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Research ArticleArticle

GLUCURONIDATION OF TCC AND ITS METABOLITES

N. H. Schebb, B. Franze, R. Maul, A. Ranganathan and B. D. Hammock
Drug Metabolism and Disposition January 1, 2012, 40 (1) 25-31; DOI: https://doi.org/10.1124/dmd.111.042283
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