Presentations of tetramethylammonium hydroxide dermal exposure and the valuable potential of diphoterine solution in decontamination: a retrospective observational study.

BACKGROUND: Tetramethylammonium hydroxide (TMAH) is a quaternary ammonium compound that is both a base corrosive and a cholinergic agonist, and it is widely used in the photoelectric and semiconductor industries. It causes corrosive skin injuries and systemic cholinergic toxicity with death primarily resulting from respiratory failure without efficacious early decontamination. METHODS: A retrospective observational study was performed of all cases of TMAH exposure reported to the Taiwan Poison Control Center between July 2010 and October 2017. Retrieved medical records were independently reviewed by two trained clinical toxicologists. RESULTS: Despite immediate (< 5 min) skin decontamination with copious amounts of tap water, one patient exposed to 25% TMAH involving ≥5% of total body surface area (TBSA) developed significant systemic toxicity. Patients exposed to 25% TMAH involving ≤1% TBSA developed first-degree chemical skin injuries but no systemic toxicity. Among patients exposed to lower concentrations (≤2.38%) of TMAH, the majority only experienced first-degree chemical skin injuries without systemic signs. Patients exposed to 0.5% TMAH involving nearly their entire TBSA developed no chemical skin injuries or systemic toxicity. All patients who had only first-degree chemical skin injuries did not develop systemic toxicity after exposure to either 2.38% or 25% TMAH. CONCLUSIONS: TMAH acts as an alkaline corrosive and cholinergic agonist. Systemic signs attributable to TMA+ can rapidly lead to respiratory failure and death after dermal exposure. We have demonstrated that an amphoteric solution may be efficacious for skin decontamination on-site immediately to prevent or ameliorate such toxicity. This practice especially carries a valuable potential in managing victims (patients) who have been exposed to those chemicals with immediate life-threatening toxicity (e.g. TMAH), suggesting that its early utilization deserves further study.

Adolescence versus adulthood: Differences in basal mesolimbic and nigrostriatal dopamine transmission and response to drugs of abuse.

Epidemiological studies have shown that people who begin experimenting drugs of abuse during adolescence are more likely to develop substance use disorders, and the earliest is the beginning of their use, the greatest is the likelihood to become dependent. Understanding the neurobiological changes increasing adolescent vulnerability to drug use is becoming imperative. Although all neurotransmitter systems undergo relevant developmental changes, dopamine system is of particular interest, given its role in a variety of functions related to reward, motivation, and decision making. Thus, in the present study, we investigated differences in mesolimbic and nigrostriatal dopamine transmission between adolescent (5, 6, 7 weeks of age) and adult rats (10-12 weeks of age), in basal conditions and following drug challenge, by using in vivo brain microdialysis. Although no significant difference between adolescents and adults was observed in dopamine basal levels in the nucleus accumbens (NAc)shell and core, reduced DA levels were found in the dorsolateral striatum (DLS) of early and mid-adolescent rats. Adolescent rats showed greater increase of dopamine in the NAc shell following nicotine (0.4 mg/kg), THC (1.0 mg/kg), and morphine (1.0 mg/kg), in the NAc core following nicotine and morphine, and in the DLS following THC, morphine, and cocaine (10 mg/kg). These results, while adding new insight in the development and functionality of the dopamine system during different stages of adolescence, might provide a neurochemical basis for the greater vulnerability of adolescents to drugs of abuse and for the postulated gateway effect of nicotine and THC toward abuse of other illicit substances.

Resting-state functional connectivity between the dorsal anterior cingulate cortex and thalamus is associated with risky decision-making in nicotine addicts.

Nicotine addiction is associated with risky behaviors and abnormalities in local brain areas related to risky decision-making such as the dorsal anterior cingulate cortex (dACC), anterior insula (AI), and thalamus. Although these brain abnormalities are anatomically separated, they may in fact belong to one neural network. However, it is unclear whether circuit-level abnormalities lead to risky decision-making in smokers. In the current study, we used task-based functional magnetic resonance imaging (fMRI) and examined resting-state functional connectivity (RSFC) to study how connectivity between the dACC, insula, and thalamus influence risky decision-making in nicotine addicts. We found that an increase in risky decision-making was associated with stronger nicotine dependence and stronger RSFC of the dACC-rAI (right AI), the dACC-thalamus, the dACC-lAI (left AI), and the rAI-lAI, but that risky decision-making was not associated with risk level-related activation. Furthermore, the severity of nicotine dependence positively correlated with RSFC of the dACC-thalamus but was not associated with risk level-related activation. Importantly, the dACC-thalamus coupling fully mediated the effect of nicotine-dependent severity on risky decision-making. These results suggest that circuit-level connectivity may be a critical neural link between risky decision-making and severity of nicotine dependence in smokers.

Tobacco smoke and pregnancy: segmental analysis of nicotine in maternal hair.

The investigation assessed nicotine metabolism prior to and during pregnancy in relation to different maternal smoking habits. It included segmental hair analysis in 3 groups of postpartum women: 32 active smokers, 35 passive smokers, and 19 unexposed nonsmokers. Maternal hair at least 12 cm long was collected after delivery and was divided into four 3-cm-long segments representing each trimester of pregnancy and the 3 months prior to pregnancy. Hair nicotine concentration was determined by gas chromatography-mass spectrometry. Nicotine levels were the highest in the 3-month period before pregnancy and it gradually decreased with advancing gestation in all study groups. These results suggest that when assessing tobacco exposure as measured by nicotine in hair, metabolic changes of nicotine during pregnancy should be taken into consideration.

Nicotine intake and smoking topography in smokers with bipolar disorder.

OBJECTIVES: Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized. METHODS: We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included. RESULTS: There were no differences between the BPD and CON groups in baseline smoking characteristics or serum nicotine or cotinine levels. Fifty-one smokers with BPD (68.9%) were taking one of the following mood stabilizers: valproic acid, lamotrigine, carbamazepine, oxcarbazepine, lithium, or topiramate. The 3-hydroxycotinine-to-cotinine ratio, a marker of cytochrome P450 2A6 (CYP2A6) metabolic activity, was significantly higher in BPD versus CON and versus SCZ (0.68 versus 0.49 versus 0.54; p =0.002). The difference between groups, however, was no longer significant when the analysis was repeated with those taking hepatic enzyme-inducing drugs (carbamazepine, oxcarbazepine, and topiramate) included as a covariate. The time between puffs, or interpuff interval (IPI), was shorter in BPD versus CON by an average of 3.0sec (p<0.05), although this was no longer significant when we removed smokers from the analysis of those taking hepatic enzyme inducers. CONCLUSIONS: Smokers with BPD are not different from CON on most measures of nicotine intake and smoking topography. We found an increased rate of nicotine metabolism in smokers taking mood stabilizers that are hepatic enzyme inducers, including carbamazepine, oxcarbazepine, and topiramate. Smokers with rapid nicotine metabolism might be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood and brain, and may have more difficulty in quitting smoking, although this requires further study.

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens.

Nicotine addiction and alcohol use disorders are very widespread and often occur together. Currently, there is no single drug approved for the simultaneous treatment of both conditions. Although these conditions share common genetic factors, the molecular mechanisms underlying their comorbidity are unknown. We have previously shown that mice lacking protein kinase C epsilon (PKCε) show decreased ethanol self-administration and reward as well as increased aversion to ethanol. Here we find that Prkce(-/-) mice self-administer less nicotine and show decreased conditioned place preference for nicotine compared with wild-type mice. In Prkce(-/-) mice, these behaviors are associated with reduced levels of α(6) and ß(3) nicotinic receptor subunit mRNA in the ventral midbrain and striatum as well as a functional deficit in cholinergic modulation of dopamine release in nucleus accumbens. Our results indicate that PKCε regulates reward signaling through α(6)-containing nicotinic receptors and suggest that PKCε could be a target for the treatment of comorbid nicotine and alcohol addictions.

Binge drinking +/- chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female Wistar rats.

AIMS: The effect of 'binge drinking' coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies. METHODS AND RESULTS: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a 'binge-type' regime for 3 weeks, +/- nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of ethanol. In contrast, the male adult rats showed no changes in basal glutamate content but exhibited a dose-dependent increase in NAc glutamate after further doses of ethanol. NAc arginine basal levels decreased significantly in both male and female adult rats after further doses of ethanol. Co-administration of nicotine modified the toxicity of ethanol as exemplified by diminishment of both the basal NAc glutamate release as well as modifying the release of this excitatory amino acid after further ethanol doses, particularly in female rats. In addition, the marked changes in arginine release after further ethanol doses were less evident. There was no evidence for increased hydroxyl radical production in the NAc after 'binge drinking' +/- nicotine. CONCLUSION: There appeared to be a greater vulnerability to ethanol toxicity in female adult rats after 'binge drinking'. It remains unclear whether the increased release of glutamate during the microdialysis evokes activation of inducible nitric oxide synthase (iNOS), which would utilize arginine in the formation of nitric oxide.

High-throughput simultaneous analysis of buprenorphine, methadone, cocaine, opiates, nicotine, and metabolites in oral fluid by liquid chromatography tandem mass spectrometry.

A method for simultaneous determination of buprenorphine (BUP), norbuprenorphine (NBUP), methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine, benzoylecgonine (BE), ecgonine methyl ester (EME), anhydroecgonine methyl ester (AEME), morphine, codeine, 6-acetylmorphine (6AM), heroin, 6-acetylcodeine (6AC), nicotine, cotinine, and trans-3'-hydroxycotinine (OH-cotinine) by liquid chromatography tandem mass spectrometry in oral fluid (OF) was developed and extensively validated. Acetonitrile (800 µL) and OF (250 µL) were added to a 96-well Isolute-PPT+protein precipitation plate. Reverse-phase separation was achieved in 16 min and quantification was performed by multiple reaction monitoring. The assay was linear from 0.5 or 1 to 500 µg/L. Intraday, interday, and total imprecision were less than 13% (n = 20), analytical recovery was 92-114% (n = 20), extraction efficiencies were more than 77% (n = 5), and process efficiencies were more than 45% (n = 5). Although ion suppression was detected for EME, cocaine, morphine, 6AC, and heroin (less than 56%) and enhancement was detected for BE and nicotine (less than 316%), deuterated internal standards compensated for these effects. The method was sensitive (limit of detection 0.2-0.8 µg/L) and specific (no interferences) except that 3-hydroxy-4-methoxyamphetamine interfered with AEME. No carryover was detected, and all analytes were stable for 24 h at 22 °C, for 72 h at 4 °C, and after three freeze-thaw cycles, except cocaine, 6AC, and heroin (22-97% loss). The method was applied to 41 OF specimens collected throughout pregnancy with a Salivette® OF collection device from an opioid-dependent BUP-maintained pregnant woman. BUP ranged from 0 to 7,400 µg/L, NBUP from 0 to 71 µg/L, methadone from 0 to 3 µg/L, nicotine from 32 to 5,020 µg/L, cotinine from 125 to 508 µg/L, OH-cotinine from 11 to 51 µg/L, cocaine from 0 to 419 µg/L, BE from 0 to 351 µg/L, EME from 0 to 286 µg/L, AEME from 0 to 7 µg/L, morphine from 0 to 22 µg/L, codeine from 0 to 1 µg/L, 6AM from 0 to 4 µg/L, and heroin from 0 to 2 µg/L. All specimens tested negative for EDDP and 6AC. This method permits a fast and simultaneous quantification of 16 drugs and metabolites in OF, with good selectivity and sensitivity.

[Genetic aspects of smoking and impact on clinical care]. / Aspects génétiques de la consommation de tabac et prise en charge clinique.

Tobacco smoking is a major public health issue and a better understanding of tobacco addiction represents an important challenge. Many factors are involved in tobacco addiction, including genetic factors. Taking them into account in smoking cessation programs would allow to better adapt these programs to individual characteristics and improve their rate of success. Given enzymatic induction by tobacco smoke, smoking cessation can nevertheless have important consequences on the metabolism of some drugs, that have to be taken into consideration. Here we present different clinical and genetic aspects of smoking and of smoking cessation. A dose adjustment of drugs influenced by tobacco smoke is proposed when quitting smoking.

Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics.

Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.

Guidelines on nicotine dose selection for in vivo research.

RATIONALE: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure. OBJECTIVES: This review capitalizes on the authors' collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. RESULTS: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses. CONCLUSIONS: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.

BACKGROUND AND OBJECTIVE: The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously. METHODS: Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12. RESULTS: On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1. CONCLUSIONS: We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.

Determinants of the rate of nicotine metabolism and effects on smoking behavior.

BACKGROUND: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. METHODS: We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. RESULTS: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04). CONCLUSION: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations.

Human cytochrome P450 (CYP) 2A6 metabolizes nicotine to cotinine and is a possible modulator of nicotine addiction. Quantitative and qualitative differences in nicotine addiction have been observed between ethnic groups. However, there are few data on the ethnic influences of the CYP2A6-nicotine metabolism relationship, particularly with regard to black subjects. We determined the nicotine metabolism and CYP2A6 genotype in 176 white subjects and 160 black subjects, comparing them with our previous data from 209 Korean subjects and 92 Japanese subjects. Large interindividual differences were observed in the cotinine/nicotine ratios in plasma calculated as an index of nicotine metabolism in white subjects (range, 0.6-36.5) and in black subjects (range, 0.9-30.4). No ethnic difference in the metabolic ratio was observed among white subjects (mean, 7.2 +/- 5.0), black subjects (mean, 7.1 +/- 4.7), and Korean subjects (mean, 8.7 +/- 11.9), whereas Japanese subjects showed a significantly (P < .005) lower metabolic ratio (mean, 3.8 +/- 3.1) compared with the other populations. Women showed significantly (P < .05) higher metabolic ratios than men in the black population (8.0 +/- 5.3 versus 6.0 +/- 3.7). Obvious ethnic differences in the CYP2A6 alleles were observed among these 4 populations. The combined frequencies of the alleles lacking or showing reduced enzymatic activity (CYP2A6*2, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*9, CYP2A6*10, CYP2A6*11, CYP2A6*17, CYP2A6*19, and CYP2A6*20) were 9.1%, 21.9%, 42.9%, and 50.5% in white, black, Korean, and Japanese subjects, respectively. These CYP2A6 alleles were associated with reduced nicotine metabolism. Among the homozygotes of CYP2A6*1, interindividual and ethnic differences in the metabolic ratio were still observed. Thus some factors other than genetic ones might also contribute to the interindividual and ethnic differences. This comprehensive study of 4 populations extends our understanding of nicotine metabolism and the impact of genetic polymorphisms of the CYP2A6 gene.

Environmental tobacco smoke and risk of spontaneous abortion.

BACKGROUND: Studies of exposure to environmental tobacco smoke (ETS) and risk of spontaneous abortion are limited to a few studies of self-reported exposure, and the results have been inconsistent. The aim of this study was to investigate risk of early spontaneous abortion related to ETS and active smoking as defined by plasma cotinine levels. METHODS: We conducted a population-based case-control study in Uppsala County, Sweden, between January 1996 and December 1998. Cases were 463 women with spontaneous abortion at 6 to 12 completed weeks of gestation, and controls were 864 pregnant women matched to cases according to the week of gestation. Exposure status was defined by plasma cotinine concentrations: nonexposed, <0.1 ng/mL; ETS-exposed, 0.1-15 ng/mL; and exposed to active smoking, >15 ng/mL. Multivariable analysis was used to estimate the relative risk of spontaneous abortion associated with exposure to ETS and active smoking. RESULTS: Nineteen percent of controls and 24% of cases were classified as having been exposed to ETS. Compared with nonexposed women, risk of spontaneous abortion was increased among both ETS-exposed women (adjusted odds ratio = 1.67; 95% confidence interval = 1.17-2.38) and active smokers (2.11; 1.36-3.27). We could not show a differential effect of exposure to ETS or active smoking between normal and abnormal fetal karyotype abortions. CONCLUSIONS: Nonsmoking pregnant women exposed to ETS may be at increased risk of spontaneous abortion. Given the high prevalence of ETS exposure, the public health consequences of passive smoking regarding early fetal loss may be substantial.

Limited modulation of the transport activity of the human multidrug resistance proteins MRP1, MRP2 and MRP3 by nicotine glucuronide metabolites.

The human ATP-binding cassette proteins MRP1 (ABCC1), MRP2 (ABCC2) and MRP3 (ABCC3) are active transporters of antineoplastic drugs as well as conjugated metabolites and other organic anions. In addition to being substrates, many glucuronide, glutathione and sulfate conjugates can also inhibit the transport activities of these MRP-related proteins, sometimes in a glutathione (GSH)-dependent manner. Nicotine is the major addictive component of cigarette smoke. Three glucuronide metabolites of this compound have been identified in vivo: nicotine-N-glucuronide, cotinine-N-glucuronide and trans-hydroxycotinine-O-glucuronide. In this study, we first chemically synthesized trans-hydroxycotinine-O-glucuronide and then tested the ability of this compound, nicotine-N-glucuronide and cotinine-N-glucuronide to modulate the vesicular transport of several organic anions by MRP1, MRP2 and MRP3. We observed that none of the three metabolites at concentrations up to 100muM significantly affected organic anion transport by MRP1 or MRP2, either in the absence or presence of GSH. MRP3-mediated transport of 17beta-estradiol 17-(beta-d-glucuronide) and methotrexate were partially inhibited by trans-hydroxycotinine-O-glucuronide (300 microM) (by 70% and 50%, respectively), whereas nicotine-N-glucuronide and cotinine-N-glucuronide had no effect. We conclude that the physiological functions of MRP1, MRP2 and MRP3 are not likely to be substantially affected by nicotine glucuronide metabolites at concentrations achievable in human serum.

Metabolism and disposition kinetics of nicotine.

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.