A physiologically based pharmacokinetic model for nicotine and cotinine in man

Abstract

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided; chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.

Measuring tobacco smoke exposure: quantifying nicotine/cotinine concentration in biological samples by colorimetry, chromatography and immunoassay methods

“…The presence of other compounds should not interfere in the estimation of the marker and the marker should not be influenced by environmental sources other than tobacco smoke. The markers used for assessing the smoking status of individuals, and the matrices in which these markers have been estimated are: nicotine (plasma, saliva, and urine) [21,[44][45][46]; carbon monoxide (expired air) [47,48]; carboxyhemoglobin (blood) [21,49]; thiocyanate ion (plasma, saliva, and urine) [21,49,[50][51][52][53][54][55]; and cotinine (plasma, saliva, and urine) [43,45,52,56].…”

“…It is present in a relatively large amount in a typical cigarette (1-2 mg per cigarette). It is absorbed and is measurable in both active and passive smokers [44,45]. However, nicotine levels in the blood fluctuate and the duration of urinary nicotine excretion is short [46].…”

“…However, nicotine levels in the blood fluctuate and the duration of urinary nicotine excretion is short [46]. Also, the half-life of nicotine is about two hours and hence it is poorly suited as a marker for monitoring chronic exposure [45].…”

Simple, rapid and sensitive assay method for simultaneous quantification of urinary nicotine and cotinine using gas chromatography–mass spectrometry

“…However, none of these biomarkers serve as good indicators due to lack of either specificity or sensitivity for the detection of tobacco smoke exposure [4][5][6][7][8]. On the other hand, nicotine, which is the main compound in the cigarette smoke is rapidly and extensively metabolized into several metabolites in human and is therefore not a suitable biomarker [9,10]. One of the major metabolites for nicotine is cotinine.…”

Doses and lung burdens of environmental tobacco smoke constituents in nonsmoking workplaces

“…Distributions for these parameters were determined based on a review of the literature. The half -life of nicotine in the body was assumed to be a triangular distribution with a minimum value of 1 h, a most likely value of 2 h, and a maximum value of 4 h (Benowitz et al, 1982;Feyerabend et al, 1985;Robinson et al, 1992;Zevin et al, 1997 ). The fraction of nicotine absorbed was assumed to be uniformly distributed between 0.6 and 0.8 ( Armitage et al, 1975;Russell and Feyerabend, 1978;Benowitz and Jacob, 1987;Iwase et al, 1991;Molander et al, 1996 ).…”