Pathways of Nicotine and Cotinine Metabolism

Nicotine is extensively metabolized to a nnmber of metabolites (Fig. 3) by the liver. Six primary metabolites of nicotine have been identified. Qnantitatively, the most important metabolite of nicotine in most mammalian species is the lactam derivative, cotinine. In humans, about 70-80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated primarily by CYP2A6 to produce nicotine-A -iminium ion, which is in equilibrium with 5 -hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminiiim ion has received considerable interest since it is an alkylating agent and, as such, could play a role in the pharmacology of nicotine (Shigenaga etal. 1988). 

In addition to oxidation of the pyrrolidine ring, nicotine is metabolized by two nonoxidative pathways, methylation of the pyridine nitrogen giving nicotine isomethonium ion (also called N-methylnicotinium ion) and glucuronidation. 

Nicotine glucmonidation results in an N-quatemary glucmonide in humans (Benowitz et al. 1994). This reaction is catalyzed by uridine diphosphate-glucuronosyltransferase (UGT) enzyme(s) producing (5)-nicotine-N-P-glucmonide. About 3-5% of nicotine is converted to nicotine glucuronide and excreted in urine in humans. 

Although on average about 70-80% of nicotine is metabolized via the cotinine pathway in humans, only 10-15% of nicotine absorbed by smokers appears in the urine as unchanged cotinine (Benowitz et al. 1994). Six primary metabolites of cotinine have been reported in humans 3 -hydroxycotinine (McKennis et al. 1963 Neurath et al. 1987), 5 -hydroxycotinine (also called allohydroxycotinine) (Neurath 1994), which exists in tautomeric equilibrium with the open chain derivative 

4-oxo-4-(3-pyridyl)-Af-methylbutanamide, cotinine A -oxide, cotinine methonium ion, cotinine glucuronide, and norcotinine (also called demethylcotinine). 

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