Metabolism and Disposition Kinetics of Nicotine

Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco Genreral Hospital Medical Center, and the Department of Medicine, University of California, San Francisco, Box 1220, San Francisco, CA 94143-1220, USA.
Pharmacological Reviews (Impact Factor: 17.1). 04/2005; 57(1):79-115. DOI: 10.1124/pr.57.1.3
Source: PubMed


Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.

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Available from: Janne Hukkanen, Oct 19, 2015
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    • "Many nicotine metabolites have been identified with cotinine representing 75% of urinary excretion. The minor metabolites and their excreted urinary percentages are: 4-oxo-4(3-pyridyl)butanoic acid and 4-hydroxy-4-(3-pyridyl)butanoic acid 11%, nicotine N ′ -oxide 5.5%, nicotine glucuronide 4%, nornicotine 0.6%, other 3.9% [39]. Nicotine is converted by liver enzyme CYP P450 2A6 to cotinine, the principal metabolite. "
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    ABSTRACT: Here we present a review of the pathophysiology of tobacco smoking on intracranial aneurysms, self-reported smoking status in these patients, screening tools and assays available for assessing active nicotine use, means of impacting smoking cessation rates, and the potential impact of smoking cessation on risk of rupture and recurrence of treated intracranial aneurysms. A literature search using PubMed was done to identify all English language studies relating to tobacco use and intracranial aneurysms, smoking and subarachnoid hemorrhage, nicotine breakdown products, and smoking cessation in neurosurgery. Results from the studies were reviewed and summarized. Tobacco use is an independent risk factor for formation, growth, and rupture of intracranial aneurysms. The pathogenesis of aneurysm formation is complex, and related to increased wall shear stress, endothelial dysfunction, atherosclerosis, and altered gene regulation. Furthermore 80% of all aneurysmal ruptures occur in patients who have used tobacco products. It is suboptimal to rely on self-reported smoking status in order to determine patient risk. Use of objective metrics for ongoing tobacco use may be indicated in selected patients, and may increase smoking cessation rates in these patients. A variety of laboratory and point-of-care tests are available for measurement of nicotine and nicotine breakdown products. Most assays in clinical practice measure the nicotine breakdown product cotinine, which constitutes 75% of nicotine metabolites excreted in the urine and has a substantial half-life of 16h, compared to nicotine's 2-h half-life. With proper identification, an astute physician may be able to assist in smoking cessation and foster improved patient care. By following recommended guidelines and prescribing pharmaceutical aid, a patient has a 2.5 times greater chance of smoking cessation compared with attempting to stop without physician assistance. Smoking increases risk for intracranial aneurysm formation, rupture, re-rupture and need for re-treatment. Measurement of nicotine breakdown products may have clinical utility in the management of patients with intracranial aneurysms. Smoking cessation interventions may be effective, and use of established smoking cessation tools use may lead to improved clinical outcomes in these patients. The effects of smoking cessation efforts on smoking cessation and intracranial aneurysm outcomes is a fertile field for future investigation. Copyright © 2015 Elsevier B.V. All rights reserved.
    Clinical neurology and neurosurgery 10/2015; 137. DOI:10.1016/j.clineuro.2015.06.016 · 1.13 Impact Factor
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    • "Based on 20 % oral bioavailability of nicotine (Hukkanen et al. 2005) and assuming linear kinetics, an oral dose of 60 mg would give rise to a plasma concentration of about 0.18 mg L -1 . The fatal nicotine intoxications suggest that the lower limit of lethal nicotine blood concentrations is about 2 mg L -1 , corresponding to 4 mg L -1 plasma, a concentration that is around 20-fold higher than that caused by intake of 60 mg nicotine. "
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    ABSTRACT: It is well known that, the explorer "Christopher Columbus" encountered tobacco in the 1400s during his earliest journey to the New World. Tobacco plant is native to North America and other parts of the Western Hemisphere. Furthermore, plant of tobacco contains nicotine and its use has a history that dates back to the earliest records of settlers arriving in America. Moreover, American Indians introduced these settlers to the tobacco plant. In various recent publications elevated nicotine concentrations have been reported to occur in many different foods and plant derived commodities (such as fungi, tea, fruit teas, spices and medicinal plants). Whereas, it is recorded that, high nicotine contaminations are also present in many plant derived products. Up till now, the causes of these contaminations are unknown and they are found in both conventional and in organic products. Thus, field and in vitro experiments are required to elucidate the origin for these nicotine contaminations. Therefore, this work aims to highlight on the nicotine contamination in some different food plants.
    German Soil Science Society (Unsere Böden – Unser Leben), 5. – 10. September 2015, München; 09/2015
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    • "Oral administration of nicotine was in the form of two pieces (4 mg + 2 mg) of cinnamon-flavored Nicorette ® gum (Johnson & Johnson Inc., Markham, Ontario, Canada). Administering a 6 mg dose was intended to result in a similar nicotine level as achieved by smokers smoking a single cigarette of average nicotine yield, producing a nicotine blood concentration of approximately 15–30 ng/ml (Hukkanen et al. 2005). Peak blood nicotine levels are achieved approximately 30 min after the beginning of the gum chewing, and the elimination half-life of nicotine is ∼120 min. "
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    ABSTRACT: Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting state electroencephalographic (EEG) oscillations. In a sample of 62 healthy nonsmoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in fronto-central regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT. This article is protected by copyright. All rights reserved.
    Genes Brain and Behavior 06/2015; 14(6). DOI:10.1111/gbb.12226 · 3.66 Impact Factor
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