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Article

Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

1
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
2
High Technology Research Center, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
3
Fujitsu Kyusyu Systems, 2-2-1 Momochihama, Sawara-Ku, Fukuoka 814-8589, Japan
4
Japan Chemical Industry Associations (JCIA), 1-4-1 Shinkawa, Chuo-Ku, Tokyo 104-0033, Japan
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2010, 7(9), 3406-3421; https://doi.org/10.3390/ijerph7093406
Received: 20 July 2010 / Revised: 20 August 2010 / Accepted: 31 August 2010 / Published: 1 September 2010
(This article belongs to the Special Issue Tobacco Smoking: Public Health, Science and Policy)
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses. View Full-Text
Keywords: physiologically based biokinetic modeling; cytochrome P450; simulation; no-observed-adverse-effect level; biomonitoring; human liver microsomes physiologically based biokinetic modeling; cytochrome P450; simulation; no-observed-adverse-effect level; biomonitoring; human liver microsomes
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MDPI and ACS Style

Yamazaki, H.; Horiuchi, K.; Takano, R.; Nagano, T.; Shimizu, M.; Kitajima, M.; Murayama, N.; Shono, F. Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling. Int. J. Environ. Res. Public Health 2010, 7, 3406-3421. https://doi.org/10.3390/ijerph7093406

AMA Style

Yamazaki H, Horiuchi K, Takano R, Nagano T, Shimizu M, Kitajima M, Murayama N, Shono F. Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling. International Journal of Environmental Research and Public Health. 2010; 7(9):3406-3421. https://doi.org/10.3390/ijerph7093406

Chicago/Turabian Style

Yamazaki, Hiroshi, Kana Horiuchi, Ryohji Takano, Taku Nagano, Makiko Shimizu, Masato Kitajima, Norie Murayama, and Fumiaki Shono. 2010. "Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling" International Journal of Environmental Research and Public Health 7, no. 9: 3406-3421. https://doi.org/10.3390/ijerph7093406

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