Category: drug_metabolism
Nicotine oxidizes to cotinine via CYP2A6 (rate-limiting; ~80% of nicotine clearance), with minor pathways to nicotine-N'-oxide (FMO3) and nornicotine. Cotinine is further hydroxylated by CYP2A6 to trans-3'-hydroxycotinine (3HC). CYP2A6 expression varies widely — slow-metabolizer variants (Asian/African genotypes) predict lower nicotine doses to reach reinforcing levels, lower lifetime cigarette consumption, easier smoking cessation, and lower lung cancer risk. The 3HC/cotinine ratio is the validated "nicotine metabolite ratio (NMR)" used to phenotype CYP2A6 activity in cessation trials.