Biomarkers Derived from Nicotine and its Metabolites: A Review
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Abstract Nicotine is the major alkaloid present in tobacco and the most frequently determined compound as a biomarker of tobacco exposure in both smokers and non-smokers exposed to environmental tobacco smoke. Current knowledge on the human metabolism and disposition kinetics of nicotine is reviewed, together with methods for the determination of nicotine and various metabolites in different human biological fluids and matrices. Only short-term biomarkers of nicotine exposure exist and long-term biomarkers of exposure such as the incorporation of nicotine and cotinine into human hair, toenails and deciduous teeth require further investigation. Determination of ‘nicotine boost’, the difference in blood nicotine concentrations that occur after smoking a single cigarette, provides an experimental indication of individual smoking behaviour, but is unsuitable for population studies. The determination of nicotine plus multiple phase I and phase II metabolites in 24-hour urine, often expressed as ‘nicotine equivalents’, provides the most accurate way to determine exposure to nicotine in smokers; however, few laboratories are equipped to perform the complex analysis required for this purpose. Nicotine equivalents can be used to estimate the uptake of nicotine from a cigarette in both individuals and in population studies. Despite recent advancements in analytical methodology and the possibility of determining multiple nicotine metabolites in various biological fluids, determination of cotinine, the major metabolite of nicotine, is likely to remain the most commonly used approach to assess exposure to tobacco smoke in both smokers and non-smokers. Representative data for cotinine in blood, saliva and urine of smokers and non-smokers are presented.Keywords:
Cotinine
Tobacco smoke
Of the various biochemical markers used to validate the smoking status of a person, nicotine and continine are considered as good markers for both active and passive smoking. In the present study an attempt was made to estimate urinary levels of nicotine and cotinine in healthy individuals from north India using different types of tobacco to identify and validate the smoking status.Twenty four hour urine sample of 130 healthy volunteers (smokers=70, passive smokers=20, tobacco chewers=20, non smokers=20) were analyzed by high-pressure liquid chromatography (HPLC) assay. Smokers were divided into different groups, viz., cigarette, bidi and hooka smokers.The mean values of nicotine (ng/ml) and cotinine (ng/ml) in urine were highest in cigarette smokers (nicotine=703.50+/-304.34; cotinine=2736.20+/-983.29), followed by hooka smokers (nicotine 548.0+/-103.47 and cotinine 2379.0+/-424.25), and bidi smokers (nicotine=268.53+/-97.62, cotinine=562.60+/-249.38). There was no correlation of nicotine or cotinine values with smoking index. In passive smokers (nicotine=109.75+/-22.33, cotinine=280.75+/-86.30) and in nonsmokers, the values were much lower (nicotine=55.00+/-13.71, cotinine=7.30+/-2.47) compared to smokers. In tobacco chewers, the values for nicotine and cotinine were 447.75+/-145.09 and 2178.30+/-334.29 respectively.All forms of tobacco users had significantly higher values compared to passive smokers and nonusers. Thus, cotinine and nicotine levels in urine may be considered as good indicators to assess the exposure to tobacco in our population.
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The residence times of nicotine and its metabolites in rat brain after acute peripheral nicotine administration were determined. We hypothesize that nicotine metabolites will reach pharmacologically significant concentrations in brain. Cotinine, nornicotine, and norcotinine were structurally identified by dual label radiochemical and gas chromatography-mass spectrometric analysis as biotransformation products of nicotine present in rat brain after s. c. injection of S(-)-nicotine. Two unidentified minor metabolites were also detected in brain. The half-lives in brain of nicotine metabolites were determined after a single s.c. injection of [2'-(14)C]-(+/-)nicotine (0.8 mg/kg) and analysis of radiolabeled metabolites by high pressure-liquid radiochromatography. The brain half-lives of nicotine, cotinine, and nornicotine were 52, 333, and 166 min, respectively. Peak brain concentrations of nicotine metabolites were 300, 70, and 7 nM for cotinine, nornicotine, and norcotinine, respectively. Even with potential accumulation of cotinine in brain after chronic nicotine administration, it is likely that the brain concentration of cotinine will be insufficient to produce neuropharmacological effects resulting from activation of nicotinic receptors to induce dopamine release. Conversely, the concentration of nornicotine in brain after acute nicotine approaches the range found to be neuropharmacologically active. It is likely that nornicotine will accumulate in brain on chronic nicotine administration based on the brain half-life of this metabolite. Importantly, nornicotine is also a major alkaloidal component of tobacco. Thus, as a consequence of tobacco use, alkaloidal and metabolically formed nornicotine may reach concentrations in brain sufficient to produce pharmacological effects.
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Nicotine is oxidized to its major metabolite, cotinine, which has a long biological half-life (19–24 h). The plasma concentration of cotinine has been used as an index of tobacco smoke exposure. Cotinine possibly increases the turnover rate of platelet-activating factor (PAF) because it is a potent activator of PAF hydrolase, and it may play a significant role in tobacco-induced arterial thrombosis. Therefore, we studied the distribution and retention of nicotine as it was metabolized to cotinine in the rat. Nicotine (1 mg/kg, 5 µCi/kg) was administered into the femoral vein of male Sprague-Dawley rats under nembutal anesthesia. At different times (5–60 min) after nicotine administration, nicotine and its metabolite, cotinine, were determined by HPLC in plasma, liver, kidney, heart and brain. Within 5–10 min after administration, nicotine concentrations reached peak values in plasma (2,160 pmol/ml) and the organs analyzed. The plasma level of nicotine decreased by 50% within 20 min (half-time) after its intravenous administration. The half-time of nicotine in the brain was about 50 min. The half-times of nicotine for the other organs were about 20–25 min. The major metabolite, cotinine, accumulated in plasma, and by about 30 min the concentrations of nicotine and cotinine in plasma were about equal (890–1,000 pmol/ml). While cotinine accumulated in plasma, nicotine was eliminated by the kidney. While the nicotine concentrations decreased with time in all organs, cotinine concentrations remained constant. These observations indicate that nicotine is renally eliminated or metabolized to cotinine while cotinine exhibits a long retention time and accumulates in plasma. This plasma accumulation may contribute to activation of PAF turnover rate and to thrombosis.
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Abstract Nicotine is the major alkaloid present in tobacco and the most frequently determined compound as a biomarker of tobacco exposure in both smokers and non-smokers exposed to environmental tobacco smoke. Current knowledge on the human metabolism and disposition kinetics of nicotine is reviewed, together with methods for the determination of nicotine and various metabolites in different human biological fluids and matrices. Only short-term biomarkers of nicotine exposure exist and long-term biomarkers of exposure such as the incorporation of nicotine and cotinine into human hair, toenails and deciduous teeth require further investigation. Determination of ‘nicotine boost’, the difference in blood nicotine concentrations that occur after smoking a single cigarette, provides an experimental indication of individual smoking behaviour, but is unsuitable for population studies. The determination of nicotine plus multiple phase I and phase II metabolites in 24-hour urine, often expressed as ‘nicotine equivalents’, provides the most accurate way to determine exposure to nicotine in smokers; however, few laboratories are equipped to perform the complex analysis required for this purpose. Nicotine equivalents can be used to estimate the uptake of nicotine from a cigarette in both individuals and in population studies. Despite recent advancements in analytical methodology and the possibility of determining multiple nicotine metabolites in various biological fluids, determination of cotinine, the major metabolite of nicotine, is likely to remain the most commonly used approach to assess exposure to tobacco smoke in both smokers and non-smokers. Representative data for cotinine in blood, saliva and urine of smokers and non-smokers are presented.
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Abstract Nicotine and a basic metabolite, cotinine, were determined in the urine by gas-liquid chromatography after intravenous administration of (—)-nicotine hydrogen (+)-tartrate to groups of male and female smokers and non-smokers in whom the urine was maintained at an acid pH. The urinary recoveries of nicotine and cotinine from male smokers fell in two groups. One showed a lower recovery of both alkaloids than was seen with male non-smokers. The other showed a similar recovery of nicotine but more cotinine than the male non-smokers. Female smokers excreted less nicotine but more cotinine than female non-smokers. More nicotine but less cotinine was excreted by female non-smokers than by male non-smokers. The results show sex dependent metabolism of nicotine occurs in non-smoking humans and that smoking causes alterations in nicotine metabolism.
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A new radiometric assay for nicotine and 12 of its metabolites disclosed that plasma nicotine and cotinine t1/2 beta were independent of dose after single intraarterial nicotine doses of 0.1, 0.5, or 1.0 mg/kg. At high doses, nicotine AUC and clearance tended to exhibit a small degree of dose dependency. The longest lived metabolites, cotinine-N-oxide and a previously unidentified metabolite now revealed to be allohydroxydemethylcotinine, persisted for 96 hr after nicotine injection, whereas cotinine was detected for only 48 hr. Cotinine, formerly considered the longest lived nicotine metabolite, serves widely as the most sensitive indicator of prior exposure to small concentrations of nicotine. The present studies disclose new, longer lasting metabolites that may perform this function more sensitively, at least in the rat. At the 3 doses of nicotine administered, plasma nicotine half-life ranged from 0.9 to 1.1 hr; total body clearance of nicotine ranged from 2.9 to 3.9 liters.hr-1.kg-1; and apparent volume of distribution of nicotine from 4.7 to 5.7 liters.kg-1. Also at these 3 doses, mean half-lives of urinary excretion of cotinine, cotinine-N-oxide, and allohydroxydemethylcotinine ranged from 4.8 to 5.3 hr, from 7.9 to 8.2 hr, and from 9.9 to 11.0 hr, respectively.
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Background: Studies on the oral route of nicotine administration in rodents make important contributions to our understanding of human nicotine use, and alternative approaches to smoking cessation. While environmental availability of oral nicotine contributes to voluntary intake and appears to drive consumption initially, solution concentration may exert more control over intake with continued exposure. Further, it is believed that female rodents consume more nicotine and show greater motivation to obtain it than males. Objectives: The purpose of our study was to determine voluntary oral nicotine intake patterns following continuous exposure to relatively high concentrations in male and female rats, employing a multiple bottle approach, and to describe the relationship between oral nicotine consumption and sera cotinine. Methods: Using five bottles, adult Sprague–Dawley rats were given continuous access to water and 15 μg/ml nicotine solutions or water and 15 and 30 μg/ml nicotine solutions for 2 weeks; blood serum was analyzed for cotinine. Results: Rats consistently consumed oral nicotine and female rats ingested more nicotine than males, even at relatively high concentrations. Yet, when both concentrations were presented simultaneously, oral nicotine intake did not exceed that of water, thus overriding an environmental, or multiple-bottle, effect. Cotinine was systemically circulated following first-pass hepatic metabolism of nicotine at early, but not at later stages of nicotine exposure. Conclusions: Our findings suggest rats will readily and voluntarily ingest considerably higher doses of nicotine than previously reported resulting in initial systemic cotinine, and trends toward sex differences are mitigated by solution concentration.
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