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Cotinine effects on nicotine metabolism

S Zevin¹, P Jacob, N Benowitz

¹Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, California 94110, USA.

Clinical Pharmacology and Therapeutics

|June 1, 1997

Summary

Cotinine does not inhibit nicotine metabolism or lower nicotine clearance in smokers. Cotinine levels can quantify environmental tobacco exposure, as its half-life differs from nicotine.

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Area of Science:

Pharmacology
Toxicology

Background:

Smokers exhibit significantly reduced nicotine clearance and half-life compared to nonsmokers.
Cotinine, the primary nicotine metabolite, accumulates with regular smoking.
Nicotine and cotinine share a common liver enzyme for metabolism, suggesting potential interaction.

Purpose of the Study:

To investigate whether cotinine inhibits nicotine metabolism.
To determine if cotinine influences nicotine clearance in smokers.

Main Methods:

A randomized, double-blind, placebo-controlled crossover study involving 12 healthy nonsmokers.
Intravenous infusions of deuterium-labeled nicotine-d2 and cotinine-d4 were administered.
Subjects received either oral cotinine treatment or a placebo, with pharmacokinetic parameters analyzed.

Main Results:

Oral cotinine administration achieved plasma levels comparable to heavy smokers.
Cotinine did not affect the disposition kinetics or clearance of nicotine.
The half-life of cotinine derived from nicotine was longer than administered cotinine, indicating tissue nicotine release.

Conclusions:

Cotinine is not the cause of reduced nicotine clearance in smokers.
Cotinine pharmacokinetics in nonsmokers are similar to smokers, validating its use for environmental tobacco exposure assessment.
Slow nicotine release from tissues likely explains the prolonged cotinine half-life observed in some individuals.

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