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Title: A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

Abstract

The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element ofmore » a dosimetry-driven risk assessment strategy for cigarette smoke constituents.« less

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1063721
Report Number(s):
PNNL-SA-92151
600306000
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Regulatory Toxicology and Pharmacology, 65(1):12-28
Additional Journal Information:
Journal Name: Regulatory Toxicology and Pharmacology, 65(1):12-28
Country of Publication:
United States
Language:
English

Citation Formats

Teeguarden, Justin G., Housand, Conrad, Smith, Jordan N., Hinderliter, Paul M., Gunawan, Rudy, and Timchalk, Charles. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans. United States: N. p., 2013. Web. doi:10.1016/J.YRTPH.2012.10.007.
Teeguarden, Justin G., Housand, Conrad, Smith, Jordan N., Hinderliter, Paul M., Gunawan, Rudy, & Timchalk, Charles. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans. United States. doi:10.1016/J.YRTPH.2012.10.007.
Teeguarden, Justin G., Housand, Conrad, Smith, Jordan N., Hinderliter, Paul M., Gunawan, Rudy, and Timchalk, Charles. Fri . "A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans". United States. doi:10.1016/J.YRTPH.2012.10.007.
@article{osti_1063721,
title = {A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans},
author = {Teeguarden, Justin G. and Housand, Conrad and Smith, Jordan N. and Hinderliter, Paul M. and Gunawan, Rudy and Timchalk, Charles},
abstractNote = {The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.},
doi = {10.1016/J.YRTPH.2012.10.007},
journal = {Regulatory Toxicology and Pharmacology, 65(1):12-28},
number = ,
volume = ,
place = {United States},
year = {2013},
month = {2}
}