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Pharmacokinetic Analysis of NNK in Sprague-Dawley Rats

Principal Investigator: Shu-Chieh Hu / Phil Yeager

Funding Mechanism: JV

ID number: C13040/E07525.01

Award Date: 8/1/2012

Institution: National Center for Toxicological Research

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] occurs naturally in cigarette smoke. It is a potent genotoxin and carcinogen and is considered to be one of the compounds responsible for the induction of lung cancer in humans exposed to tobacco smoke. Parenteral administration of NNK in laboratory animals indicates that its absorption, metabolism, and distribution occur rapidly; however, current pharmacokinetic data on NNK following inhalation are insufficient to accurately predict NNK blood distribution. The goal of this project is to evaluate the pharmacokinetic profile of NNK in rats by determining the blood and tissue distribution of NNK and metabolites following NNK administration via oral, intraperitoneal and inhalation routes. Specific aims are: (1) to establish pharmacokinetic data on the distribution of NNK following inhalation exposure; and (2) to provide pharmacokinetic data on the distribution of NNK following oral and intraperitoneal administration in rats. This will be the first complete current pharmacokinetic analysis following inhalation administration of NNK; analyses following the oral and intraperitoneal administrations will allow a comparison with the few previous studies using oral and intraperitoneal administration of NNK. Data developed by this project will help determine the risk associated with exposure to specific levels of NNK found in cigarette smoke; this data may inform the design of future inhalation toxicology studies that will determine the dose-response of NNK for respiratory and other target-organ toxicities.


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