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Article

Metabolism and Disposition Kinetics of Nicotine

Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, and the Departments of Medicine and Psychiatry, University of California, San Francisco, California

Abstract

I. Introduction

II. Nicotine and Related Alkaloids in Tobacco Products

III. Absorption of Nicotine from Tobacco Smoke and Nicotine Medications

IV. Distribution of Nicotine in Body Tissues

V. Nicotine and Cotinine Blood Levels during Tobacco Use and Nicotine Replacement Therapy

VI. Metabolism of Nicotine

A. Primary Metabolites of Nicotine

B. Cotinine Metabolism

C. Quantitative Aspects of Nicotine Metabolism

D. Liver Enzymes Responsible for Nicotine and Cotinine Metabolism

1. Cytochrome P450 Enzymes.

2. Aldehyde Oxidase.

3. Flavin-Containing Monooxygenase 3.

4. Amine N-Methyltransferase.

5. UDP-Glucuronosyltransferases.

E. Genetic Variations in Nicotine Metabolizing Enzymes

1. CYP2A6 Polymorphisms.

2. Polymorphisms in Other Enzymes.

F. Extrahepatic Nicotine Metabolism

G. Factors Influencing Nicotine Metabolism

1. Physiological Influences.

a. Diet and Meals.

b. Age.

c. Chronopharmacokinetics of Nicotine.

d. Gender-Related Differences in Nicotine Metabolism.

2. Pathological Conditions.

3. Medications.

a. Inducers.

b. Inhibitors.

4. Smoking.

a. Inhibiting Effect on Nicotine Clearance.

b. Inducing Effect of Smoking on Glucuronidation.

5. Racial and Ethnic Differences.

VII. Excretion

A. Renal Excretion

B. Excretion in Feces and Sweat

VIII. Species Differences in Nicotine Metabolism

IX. Metabolism of Minor Alkaloids of Tobacco

X. Pharmacokinetics and Metabolism of Nicotine Analogs

XI. Conclusions and Areas for Further Study

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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