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

Hiroshi Yamazaki, Kana Horiuchi, Ryohji Takano, Taku Nagano, Makiko Shimizu, Masato Kitajima, Norie Murayama and Fumiaki Shono
Additional contact information
Hiroshi Yamazaki: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
Kana Horiuchi: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
Ryohji Takano: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
Taku Nagano: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
Makiko Shimizu: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
Masato Kitajima: Fujitsu Kyusyu Systems, 2-2-1 Momochihama, Sawara-Ku, Fukuoka 814-8589, Japan
Norie Murayama: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
Fumiaki Shono: Japan Chemical Industry Associations (JCIA), 1-4-1 Shinkawa, Chuo-Ku, Tokyo 104-0033, Japan

IJERPH, 2010, vol. 7, issue 9, 1-16

Abstract: 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.

Keywords: physiologically based biokinetic modeling; cytochrome P450; simulation; no-observed-adverse-effect level; biomonitoring; human liver microsomes (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2010
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.mdpi.com/1660-4601/7/9/3406/pdf (application/pdf)
https://www.mdpi.com/1660-4601/7/9/3406/ (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:gam:jijerp:v:7:y:2010:i:9:p:3406-3421:d:9466

Access Statistics for this article

IJERPH is currently edited by Ms. Jenna Liu

More articles in IJERPH from MDPI
Bibliographic data for series maintained by MDPI Indexing Manager ().