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Research ArticleArticle

Metabolism and Disposition of [14C]1-Nitronaphthalene in Male Sprague-Dawley Rats

Jason S. Halladay, John-Michael Sauer and I. Glenn Sipes
Drug Metabolism and Disposition December 1999, 27 (12) 1456-1465;
Jason S. Halladay
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John-Michael Sauer
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I. Glenn Sipes
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Abstract

In rats and mice, 1-nitronaphthalene (1-NN) produces both lung and liver toxicity. Even though these toxicities have been reported, the metabolism and disposition of 1-NN have not been elucidated. Therefore, studies were performed to characterize its fate after i.p. and i.v. administration to male Sprague-Dawley rats. After i.p. administration of [14C]1-NN (100 mg/kg; 60 μCi/kg), 84% of the dose was eliminated in the urine and feces by 48 h. At 96 h, 60% of the dose was recovered in the urine, 32% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. The terminal phase rate constant (kterm) of 1-NN was 0.21 h−1, the terminal phase half-life (T1/2,term) was 3.40 h, and the systemic bioavailability was 0.67. When administered i.v. (10 mg/kg; 120 μCi/kg), 85% of the dose was eliminated in the urine and feces by 24 h. At the end of the study (96 h), 56% of the dose was recovered in the urine, 36% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. Interestingly, 88% of the dose was secreted into bile by 8 h. Thekterm was 0.94 h−1 and theT1/2,term was 0.77 h. The major urinary metabolite after both routes of administration wasN-acetyl-S-(hydroxy-1-nitro-dihydronaphthalene)-l-cysteine. Other urinary metabolites identified include hydroxylated, dihydroxylated, glucuronidated, sulfated, and reduced metabolites, as well as dihydrodiol. The major biliary metabolite was hydroxy-glutathionyl-1-nitro-dihydronaphthalene. These data show that 1-NN undergoes extensive metabolism and enterohepatic recirculation, and the majority of the dose is eliminated in the urine.

Footnotes

  • Send reprint requests to: Dr. I. Glenn Sipes, Department of Pharmacology and Toxicology, College of Pharmacy, P.O. Box 210207, The University of Arizona, Tucson, AZ 85721-0207. E-mail:sipes{at}pharmacy.arizona.edu

  • This research was supported by National Institute on Environmental Health Sciences-sponsored Southwest Environmental Health Sciences Center Grant P30-ES-06694.

  • Abbreviations used are::
    1-NN
    1-nitronaphthalene
    JVC
    jugular vein cannula
    AUC
    area under the blood concentration-time curve from zero to time infinity
    CL
    apparent clearance
    F
    bioavailability
    CID
    collision-induced dissociation
    GC
    gas chromatography
    MS
    mass spectrometry
    MS-MS
    tandem mass spectrometry
    RT
    retention time
    LC
    liquid chromatography
    • Received June 7, 1999.
    • Accepted August 31, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (12)
Drug Metabolism and Disposition
Vol. 27, Issue 12
1 Dec 1999
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Research ArticleArticle

Metabolism and Disposition of [14C]1-Nitronaphthalene in Male Sprague-Dawley Rats

Jason S. Halladay, John-Michael Sauer and I. Glenn Sipes
Drug Metabolism and Disposition December 1, 1999, 27 (12) 1456-1465;

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Research ArticleArticle

Metabolism and Disposition of [14C]1-Nitronaphthalene in Male Sprague-Dawley Rats

Jason S. Halladay, John-Michael Sauer and I. Glenn Sipes
Drug Metabolism and Disposition December 1, 1999, 27 (12) 1456-1465;
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