Recent studies of nicotine metabolism in humans

doi:10.1016/0091-3057(88)90453-4

Pharmacology Biochemistry and Behavior

Volume 30, Issue 1, May 1988, Pages 249-253

https://doi.org/10.1016/0091-3057(88)90453-4 Get rights and content

Abstract

Recent studies of quantitative and qualitative aspects of nicotine metabolism, and the use of metabolic data for estimating nicotine intake in humans are discussed. Previously reported methodology for determining nicotine bioavailability has been improved by using stable isotope-labeled nicotine administered intravenously. Combined gas chromatography-mass spectrometry with selected ion monitoring has been used to simultaneously determine concentrations of isotopically-labled nicotine and tobacco-derived nicotine in blood. Nicotine intake from cigarette smoking was estimated from clearance of labeled nicotine and blood concentrations of tobacco-derived nicotine. Progress in elucidating the metabolic profile of nicotine in humans, and the use of nicotine metabolites as markers of tobacco smoke consumption is summarized.

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2-Hydroxymethylpyridines undergo nickel-catalyzed hydrogenolysis upon activation with a chlorophosphate. Reactions employ diethylzinc and are proposed to proceed through secondary benzylzinc reagents. Quenching with deuteromethanol provides straightforward incorporation of a deuterium label in the benzylic position. Intramolecular conjugate additions with α,β-unsaturated esters are also demonstrated and support the intermediacy of a benzylzinc complex.
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After isolation the cell pellets were flash-frozen and stored at −80 °C until further processing. Cotinine is the main metabolite of nicotine [43]. Due to its longer half-life of 20 h, in contrast to nicotine which has a much shorter half-life of about 20 min, it is widely used as a biomarker of nicotine exposure.
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Simple, fast and sensitive LC-MS/MS analysis for the simultaneous quantification of nicotine and 10 of its major metabolites
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Citation Excerpt :
However, the new method revealed an underestimation by 50% for NorCot and an overestimation for OH-Cot-Gluc by 40% as compared to the previous method. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDP-glyucuronosyltransferase (UGT) and flavin containing monooxygenase (FMO) [9,45,46]. Urinary nicotine and metabolite concentrations have been widely used to determine nicotine equivalents as an estimate of the nicotine dose that is taken up by smoking or use of other tobacco and nicotine products [37,28,32,47].
Urinary determination of nicotine metabolites provides an ideal tool for the quantitative assessment of the tobacco use-related nicotine dose, provided that the considered metabolites comprise a large share of the amount taken up. A method based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) was developed for the sensitive, fast and robust analysis of nicotine and 10 major nicotine metabolites (“Nic+10”), including cotinine, trans-3′-hydroxy-cotinine, nicotine-N-glucuronide, cotinine-N-glucuronide, trans-3′-hydroxy-cotinine-O-glucuronide, nornicotine, norcotinine, nicotine-N′-oxide, cotinine-N′-oxide and 4-hydroxy-(3-pyridyl)-butanoic acid. Corresponding deuterated internal standards were spiked prior to a simple and straightforward solid phase extraction (SPE) procedure. Liquid chromatography was performed on a reversed phase C8 column and mass-specific detection was conducted in scheduled-MRM mode. The method was validated according to FDA Guidelines, showing excellent selectivity, precision, accuracy and robustness. The limits of quantification were in the range 0.2–2.3 ng/ml for all analytes. The novel method was applied to human urine samples derived from 25 smoking subjects. Quantitative results were correlated against a previously used LC–MS/MS method and compared to reports from the literature. The relative molar profile of nicotine and its 10 major metabolites was in good agreement with the literature. In addition, correlation amongst the two methods was excellent for almost all analytes, whereas the accordance between both methods was moderate for hydroxy-cotinine-O-glucuronide and norcotinine. These deviations, however, could be explained. The current method allows the simultaneous determination of nicotine and its 10 major metabolites (metabolite coverage about 95% of the absorbed dose) from a small sample volume and within a reasonable amount of time. Due to its wide dynamic range, high sensitivity and high throughput capabilities, this method could serve as a powerful tool for quantifying the nicotine dose of smokers, passive smokers as well as novel tobacco and nicotine product users in clinical and epidemiological studies.
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A robust, filter analysis method was used to estimate the tar and nicotine yields for 784 subjects. Seventeen brands were chosen to represent a wide range of styles: 85 and 100 mm lengths; menthol and non-menthol; 17, 23, and 25 mm circumference; with tar yields [Federal Trade Commission (FTC) method] ranging from 1 to 18 mg. Tar bands chosen corresponded to yields of 1–3 mg, 4–6 mg, 7–12 mg, and 13+ mg.
A significant difference (p < 0.0001) in HS yields of tar and nicotine between tar bands was found. Machine-smoked yields were reasonable predictors of the HS yields for groups of subjects, but the relationship was neither exact nor linear. Neither the FTC, the Massachusetts (MA) nor the Canadian Intensive (CI) machine-smoking methods accurately reflect the HS yields across all brands. The FTC method was closest for the 7–12 mg and 13+ mg products and the MA method was closest for the 1–3 mg products. The HS yields for the 4–6 mg products were approximately midway between the FTC and the MA yields. HS nicotine yields corresponded well with published urinary and plasma nicotine biomarker studies.
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This review gives a brief overview over the major aspects of application of the nicotine alkaloid and its close derivatives in the therapy of some neurodegenerative disorders and diseases (e.g. Alzheimer's disease, Parkinson's disease, Tourette's syndrome, schizophrenia etc.). The issues concerning methods of nicotine analysis and isolation, and some molecular aspects of nicotine pharmacology are included. The natural and synthetic analogues of nicotine that are considered for medical practice are also mentioned. The molecular properties of two naturally occurring nicotine enantiomers are compared — the less-common but less-toxic (R)-nicotine is suggested as a natural compound that may find its place in pharmaceutical practice.
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Nicotine is a naturally occurring alkaloid found in many plants. The principal sources of nicotine exposure is through the use of tobacco, nicotine containing gum and nicotine replacement therapies. Nicotine is an amine composed of pyridine and pyrrolidine rings. It has been shown that nicotine crosses biological membranes and the blood brain barrier easily. The absorbed nicotine is extensively metabolized in the liver to form a wide variety of metabolites including nicotine N′-oxide and cotinine N′-oxide. These are the products of mixed function oxidase system. Nicotine is also converted to some biologically important compounds during harvesting. Among these are the nitrosamines specific to tobacco. Nicotine has been shown to affect a wide variety of biological functions ranging from gene expression, regulation of hormone secretion and enzyme activities. The objective of this study was to overview the biological effects and metabolism of nicotine.

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^☆: Supported in part by U.S. Public Health Service Grants DAO2277, CA32389 and DAO1696. Studies were carried out in part in the General Clinical Research Center (RR-00083) with support of the Division of Research Resources, National Institutes of Health.

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Recent studies of nicotine metabolism in humans☆

Abstract

J Pharm Sci

J Chromatogr

J Chromatogr

The use of biologic fluid samples in assessing tobacco smoking consumption

Metabolism, pharmacokinetics and pharmacodynamics of nicotine in man

Daily intake of nicotine during cigarette smoking

Clin Pharmacol Ther

Nicotine and carbon monoxide intake from high- and low-yield cigarettes

Clin Pharmacol Ther

Interindividual variability in the metabolism and cardiovascular effects of nicotine in man

J Pharmacol Exp Ther

Reduced tar, nicotine and carbon monoxide exposure while smoking ultralow- but not low-yield cigarettes

JAMA