cotinine

Cotinine is the major metabolite of nicotine in humans, formed in the liver and widely used as a biomarker of exposure to tobacco smoke and nicotine-containing products. It remains in the body longer than nicotine, enabling assessment of recent and past exposure.

Formation and metabolism: Nicotine is demethylated by hepatic cytochrome P450 enzymes, chiefly CYP2A6, to cotinine. Cotinine can be further oxidized to trans-3'-hydroxycotinine and other metabolites, and is excreted primarily in urine as free cotinine and cotinine glucuronide. The elimination half-life of cotinine is about 16–20 hours, with substantial interindividual variability influenced by genetics, age, pregnancy, and renal function.

Distribution and use: Cotinine is detectable in plasma or blood, urine, saliva, and hair, reflecting tobacco exposure over a longer period than nicotine. Its stability and longer half-life make it a preferred marker in clinical and epidemiological contexts. Applications include verifying smoking status, monitoring nicotine replacement therapy, and assessing secondhand smoke exposure. Analytical methods range from immunoassays for screening to LC-MS/MS methods for confirmation and quantification.

Pharmacology and safety: Cotinine has relatively low activity at nicotinic receptors compared with nicotine and is not considered a major contributor to nicotine's psychoactive effects. It is generally non-toxic at typical exposure levels and is interpreted as a biomarker rather than a pharmacologically active drug.

Genetic and population factors: Variation in CYP2A6 activity affects cotinine formation and clearance. Slow metabolizers may exhibit higher cotinine levels for longer periods, and physiological states such as pregnancy or aging can alter metabolism, affecting interpretation of cotinine measurements.