Vol. 27, Issue 12, 1456-1465, December 1999

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

Jason S. Halladay, John-Michael Sauer, and I. Glenn Sipes

Department of Pharmacology and Toxicology and Center for Toxicology, The University of Arizona, Tucson, Arizona

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 (k_term) of 1-NN was 0.21 h¹, 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 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. The k_term was 0.94 h¹ 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.