Journal Article 1)
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.
Conclusions and Areas for Further Study
In conclusion, our review has focused on the metabolism and disposition kinetics of nicotine, related tobacco alkaloids, and nicotine analogs. The metabolism and kinetics of nicotine and metabolites are being unraveled with increasing precision. The enzymes involved in the nicotine metabolism and factors affecting the interindividual differences, such as the genetic polymorphisms of CYP2A6 enzyme and the induction of nicotine metabolism by sex hormones, have been elucidated in recent years. New pathways of nicotine metabolism have been recently discovered. New methods to deliver nicotine as a medication have been developed and are being applied to treatment of nicotine-dependent smokers.
We have reviewed data on minor tobacco alkaloids and nicotine analogs that might be used therapeutically, but relatively little information has been published. However, because of similar structures, it is likely that many of the features of nicotine disposition will be shared by other nicotinic agonists. Pharmacokinetic considerations, including the importance of rate and route of dosing, are likely to influence the pharmacologic activity of these nicotine analogs, as they do for nicotine itself.
There are areas that need further research. Enzymes involved in some metabolic conversions of nicotine and metabolites are yet to be characterized. For example, P450 enzymes responsible for the metabolism of nicotine to nornicotine and conversion of cotinine to cotinine N-oxide are unknown. Furthermore, some pathways of nicotine metabolism in humans are still unresolved. Knowledge on the glucuronidation of nicotine and metabolites is less detailed than data on oxidative metabolism. The enzymes involved in the constitutive and inducible 3Ј-hydroxycotinine glucuronidation are unidentified. Human extrahepatic nicotine metabolism is poorly understood. Although CYP2A6 is the main enzyme influencing nicotine clearance, CYP2A13 and other nicotine metabolizing enzymes may have local importance in extrahepatic organs.
Some CYP2A6 alleles are yet to be studied in relation to nicotine and especially cotinine metabolism. Also ultrarapid CYP2D6 metabolizers (CYP2D6 gene amplification) should be studied in relation to nicotine and cotinine metabolism, and the role of UGT1A4 and UGT1A9 alleles in the polymorphic nicotine and cotinine glucuronidation in African-Americans should be elucidated. The effect of environmental factors such as dietary compounds, smoking, cadmium exposure, and a variety of inhibitors and inducers should be studied in more detail. The mechanisms of induction of CYP2A6 enzyme and nicotine metabolism by medications such as oral contraceptives, hormone replacement therapies, and classic inducers dexamethasone, phenobarbital, and rifampicin need further study. Understanding the mechanisms of decreased hepatic nicotine metabolism by renal failure and hepatic diseases would give more insight into the regulation of nicotine metabolism. Dietary inhibitors and inducers might partly explain the high interindividual variability in nicotine metabolism. Thus, effects of menthol, grapefruit juice, wheatgrass juice, and others should be studied. The mechanism of the effect of smoking to inhibit nicotine clearance has not been explained.
Recent advances in nicotine metabolism research have elucidated some of the causes for the wide interindividual differences in metabolic capacity. Polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance. Gender-related effects, disease states, and various inhibitors and inducers affect individual rates of nicotine metabolism. However, to date, a major portion of the variability in nicotine metabolism and clearance is unexplained. Nicotine metabolism and the factors affecting it remain intriguing subjects for future studies.