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Comparative Pharmacokinetics and in Vivo Genetic Toxicology of the Tobacco Specific Nitrosamine NNN in Rats

Comparative Pharmacokinetics and in Vivo Genetic Toxicology of the Tobacco Specific Nitrosamine NNN in Rats

Principal Investigator: Jacob Nofsinger, Mamata De and Arianne Motter

Funding Mechanism: Research Contract

ID number: HHSF223201510031I

Award Date: 9/6/2016

Institution: Battelle Memorial Institute


A study that compares the pharmacokinetic effects of N-nitrosonornicotine (NNN), a carcinogenic tobacco specific nitrosamine (TSNA), by different administration routes would be informative. The purpose of this study is to compare the pharmacokinetics of NNN via three routes of administration (inhalation, oral, and intravenous) in order to understand NNN’s in vivo genotoxic effects.  Investigators will expose six groups of rats (15 per group) to different NNN concentrations (low, medium, and high doses) via nose only inhalation (one hour exposure), intravenous injection, or oral gavage.  Blood and urine samples will be collected over 48 hours and analyzed for NNN and its metabolites (R,S)-nornicotine and N´-nitrosonornicotine-1-N-oxide.  Investigators will evaluate pharmacokinetic parameters including observed maximum serum concentration (Cmax), the time at which Cmax is observed (Tmax), apparent volume of distribution and clearance, area under the curve (AUC: last and infinity), elimination rate constant and its corresponding half-life, renal clearance, urinary excretion, and relative bioavailability. At 24 or 48 hour time points, investigators will analyze tissues for genotoxic endpoints using the Comet assay, micronucleus assay, and DNA adduct formation.  Study findings may inform the development of pharmacokinetic models for NNN.