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Research ArticleArticle

Enterohepatic Recirculation of Trichloroethanol Glucuronide as a Significant Source of Trichloroacetic Acid

Metabolites of Trichloroethylene

R. D. Stenner, J. L. Merdink, D. K. Stevens, D. L. Springer and R. J. Bull
Drug Metabolism and Disposition May 1997, 25 (5) 529-535;
R. D. Stenner
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J. L. Merdink
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D. K. Stevens
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D. L. Springer
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R. J. Bull
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Metabolites of Trichloroethylene

Abstract

Trichloroacetic acid (TCA) is a metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA do not occur until ∼12 hr after an oral dose of TRI; however, blood concentrations of TRI reach a maximum within 1 hr and is nondetectable after 2 hr. The objective of this study was to examine quantitatively enterohepatic recirculation of trichloroethanol (TCEOH) and TCA as a possible mechanism responsible for the delayed production of TCA. Jugular vein, duodenum, and bile duct-cannulated Fischer 344 rats were used, with the collection of blood, bile, urine, and feces samples after intraduodenal and intravenous dosing of animals with TRI, TCEOH, and TCA. Samples were analyzed by GC for TCA, total TCEOH, and free TCEOH. The results show that, after an intravenous dose of TCEOH (100 mg/kg), 36% of the TCEOH in blood is attributable to enterohepatic recirculation. With the same treatment, 76% of the TCA in blood is attributable to enterohepatic recirculation of metabolites. Peak concentrations of total TCEOH in bile, after an intraduodenal dose of TRI, are over 5 times higher than peak concentrations of total TCEOH in systemic blood. Peak concentrations of TCEOH glucuronide in bile are ∼200 times higher than peak concentrations of TCEOH glucuronide in systemic blood.

Footnotes

  • Send reprint requests to: R. D. Stenner, Pacific Northwest National Laboratory, P.O. Box 999, MSIN K3-54, Richland, WA 99352.

  • This work was supported in part by the U.S. Environmental Protection Agency (CR 819283-02).

  • Abbreviations used are::
    TRI
    trichloroethylene
    TCA
    trichloroacetic acid
    DCA
    dichloroacetic acid
    TCEOH
    trichloroethanol
    DCPA
    2,2-dichloropropionic acid
    F-344
    Fischer 344
    GC
    gas chromatograph
    Kelim
    elimination rate constant
    AUC
    area under the concentration-time curve
    PBPK
    physiologically based pharmacokinetic
    • Received April 5, 1996.
    • Accepted January 9, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 5
1 May 1997
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Research ArticleArticle

Enterohepatic Recirculation of Trichloroethanol Glucuronide as a Significant Source of Trichloroacetic Acid

R. D. Stenner, J. L. Merdink, D. K. Stevens, D. L. Springer and R. J. Bull
Drug Metabolism and Disposition May 1, 1997, 25 (5) 529-535;

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Research ArticleArticle

Enterohepatic Recirculation of Trichloroethanol Glucuronide as a Significant Source of Trichloroacetic Acid

R. D. Stenner, J. L. Merdink, D. K. Stevens, D. L. Springer and R. J. Bull
Drug Metabolism and Disposition May 1, 1997, 25 (5) 529-535;
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