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
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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
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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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