Nicotine is extensively metabolized in the liver and to a lesser extent in the kidney and lung. Approximately 70–80% of nicotine is metabolized to cotinine, an inactive metabolite (Benowitz et al., 1983), and about 4% is metabolized to nicotine-oxide. The metabolism of nicotine to cotinine is a two-step process likely involving CYP2A6 and aldehyde oxidase. Cotinine is further metabolized to 3'-hydroxycotinine, which undergoes renal elimination. However, nicotine, cotinine, and 3'-hydroxycotinine also undergo glucuronidation. A small fraction (10–20%) of an administered dose of nicotine is excreted as unchanged drug in the urine (Benowitz, 1996; Benowitz & Jacob, 1997; Benowitz et al., 1994).

Note to instructor(s): The daily intake of nicotine can be estimated from a measured plasma cotinine level using the following equation:
Daily dose of nicotine (in mg) = plasma cotinine concentration (ng/mL) ´ 0.08
Example: An average cotinine concentration of 300 ng/mL in a typical smoker corresponds to a daily intake of 24 mg nicotine (Benowitz & Jacob, 1994). A smoker absorbs, on average, approximately 1 mg of nicotine per cigarette (Benowitz & Jacob, 1984). It can then be estimated that a plasma cotinine level of 300 ng/mL corresponds to a daily intake of 24 cigarettes.
300 ng/mL ´ 0.08 = 24 mg = 24 cigarettes (1 mg = 1 cigarette)

Benowitz NL. Pharmacology of nicotine: Addiction and therapeutics. Annu Rev Pharmacol Toxicol 1996;36:597–613.
Benowitz NL, Jacob P 3rd. Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 1984;35:499–504.
Benowitz NL, Jacob P 3rd. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 1994;56:483–493.
Benowitz NL, Jacob P. Individual differences in nicotine kinetics and metabolism in humans. In Pharmacokinetics, Metabolism, and Pharmaceutics of Drugs of Abuse, edited by Rapaka RS, Chiang N, Martin BR. NIDA Research Monograph No. 173. USDHHS publication 97-4141, 1997.
Benowitz NL, Kuyt F, Jacob P 3rd, Jones RT, Osman AL. Cotinine disposition and effects. Clin Pharmacol Ther 1983;34:604–611.
Benowitz NL, Jacob P, Fong I, Gupta S. Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 1994;268(1):296–303.

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