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.
Organ Systems
nervous
digestive
Pathway Steps
nicotine → cotinine — via CYP2A6 — rate-limiting; ~80% of clearance. CYP2A6 is rate-limiting (~80% of nicotine clearance); cotinine’s long half-life makes it the standard biomarker of tobacco/nicotine exposure. Slow CYP2A6 metabolizers smoke less and quit more easily — a pharmacogenetic determinant of smoking behavior.
cotinine → trans-3-hydroxycotinine — via CYP2A6 (same enzyme, second step; the NMR numerator). The same CYP2A6 hydroxylates cotinine; the 3-hydroxycotinine:cotinine ratio (the nicotine metabolite ratio, NMR) is a validated in-vivo CYP2A6 activity phenotype that predicts response to nicotine-replacement versus varenicline.
nicotine → nicotine-n-oxide — via FMO3 (minor pathway). A minor FMO3-mediated route; the dominance of CYP2A6 means CYP2A6 inhibitors or loss-of-function variants substantially raise nicotine exposure and shift smoking patterns.