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, 7 (9), 3406-21

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

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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 et al. Int J Environ Res Public Health.

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-adverseeffect 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: biomonitoring; cytochrome P450; human liver microsomes; no-observed-adverse-effect level; physiologically based biokinetic modeling; simulation.

Figures

Figure 1.
Figure 1.
Approach for calculating blood-based biomonitoring equivalents for nicotine. PK, pharmacokinetics. Biomonitoring of nicotine and cotinine in plasma was carried out in male Japanese smokers.
Figure 2.
Figure 2.
PBPK model established in this study for rats and humans.
Figure 3.
Figure 3.
PK profiles in rats treated with nicotine. Nicotine (A, C) and cotinine (B, D) concentrations in blood (A, B) and urine (C, D) were determined in rats treated with nicotine (1 mg/kg/day) after the final administration of 14 daily doses.
Figure 4.
Figure 4.
Liver microsomal P450-dependent activities after nicotine treatment. Control activities were taken from liver microsomes from untreated rats. Data columns with bars present means ± SDs (n = 4). Significant differences compared with the control activities: *p < 0.05.
Figure 5.
Figure 5.
Measured and estimated blood concentrations in rats after oral administration of nicotine (A) and cotinine (B) for 14 days. Data points with bars represent means ± SDs (n = 5). The curves show the concentrations estimated by PBPK modeling.
Figure 6.
Figure 6.
Nicotine (A, C) and cotinine (B, D) concentrations modeled in humans after single (A, B) or multiple (C, D) oral administration of nicotine (1 mg/kg/day) estimated using the PBPK model. Only limited accumulation was observed for multiple doses.

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