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.
Hukkanen
Janne
J
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.
Jacob
Peyton
P
Benowitz
Neal L
NL
D000042:Absorption; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001682:Biological Availability; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D005731:Ganglionic Stimulants / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009538:Nicotine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D012907:Smoking / Q000378:metabolism*; D014018:Tissue Distribution
D005731:Ganglionic Stimulants; D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6