Metabolism and disposition of [(14)C]1-nitronaphthalene in male Sprague-Dawley rats.
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 [(14)C]1-NN (100 mg/kg; 60 microCi/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 (k(term)) of 1-NN was 0.21 h(-1), the terminal phase half-life (T(1/2,term)) was 3.40 h, and the systemic bioavailability was 0.67. When administered i.v. (10 mg/kg; 120 microCi/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. The k(term) was 0.94 h(-1) and the T(1/2,term) was 0.77 h. The major urinary metabolite after both routes of administration was N-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.
Halladay
J S
JS
Department of Pharmacology and Toxicology and Center for Toxicology, The University of Arizona, Tucson, Arizona 85721-0207, USA.
Sauer
J M
JM
Sipes
I G
IG
D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D009281:Naphthalenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D002250:Carbon Radioisotopes; D002273:Carcinogens; D009281:Naphthalenes; C016614:1-nitronaphthalene