Cotinine

Precursors and Formation. Tobaccos used for commercial products in the U.S.A, contain between 0,5 and 2,7% alkaloids. Nicotine constitutes 85-95% of the total alkaloids (14,26,27). Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine and N -formylnornicotine (Figure 6), Several of these alkaloids are secondary and tertiary amines and, as such, amenable to N-nitrosation. The N-nitrosated alkaloids identified to date in tobacco and tobacco smoke include N -nitrosonornico-tine (NNN), 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and N -nitrosoanatabine (NAT Figure 7). In model experiments, nitrosation of nicotine also yielded 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA 28). 

Korpilahde, T. et al. Smoking history and serum cotinine and thiocyanate concentrations as determinants of rheumatoid factor in non-rheumatoid subjects, Rheumatology (Oxford), 43, 1424, 2004. 

Hibberd and Gorrod incubated nicotine-A-l -(5 )-iminium (152) with hepatic homogenates prepared from mouse, rat, hamster, rabbit, guinea pig, and human fetal liver to demonstrate the involvement of such reactive chemical intermediates in the oxidation of nicotine to cotinine (151) 221). The iminium ion (152) was converted to (151) more rapidly than nicotine, thus confirming the intermediacy of the ion between nicotine and cotinine. A series of inconclusive... 

Nakajima M, Yamamoto T, Nunoya K, et al. Characterization of CYP2A6 involved in 3 -hydroxylation of cotinine in human liver microsomes. J Pharmacol Exp Ther 1996 277(2) 1010-1015. 

Waage H, Silsand T, Urdal P, et al. 1992. Discrimination of smoking status by thiocyanate and cotinine in serum, and carbon monoxide in expired air. Int J Epidemiol 21(3) 488-493. 

The primary psychoactive alkaloid in tobacco is nicotine (figure 4.9), occuring between 0.6 and 9.0% (Robbers et al. 1996 Gruenwald et al. 1998). Other alkaloids include nornicotine, N-formylnornicotine, cotinine, myosmin, )S-nicotyrine, anabasine, and nicotellin. Nicotine alone can produce the effects commonly associated with tobacco use, but other tobacco alkaloids are likely to contribute. 

Absorption occurs through the respiratory tract, orai membranes, and skin (Taylor 1996). Absorption from the stomach is iimited, uniess the acidity is reduced, because nicotine is a strong base. Between 80 and 90% of nicotine is metabolized, mainly in the liver but also the kidneys and lungs. Cotinine is the primary metabolite of nicotine, and the half-life of nicotine is about 2 hours. Elimination occurs by the kidneys, but it is also present in the breast milk of lactating women. 

Chetiyanukornkul T, Toriba A, Kizu R, Kimura K, Hayakawa K. 2004. Hair analysis of nicotine and cotinine for evaluating tobacco smoke exposure by liquid chromatography-mass spectrometry. Biomed Chromatogr 18 655. 

Xu AS, Peng LL, Havel JA, Petersen ME, Fiene JA, et al. 1996. Determination of nicotine and cotinine in human plasma by liquid chromatography-tandem mass spectrometry with atmospheric-pressure chemical ionization interface. J Chromatogr B Biomed Appl 682 249. 

An understanding of the pharmacology of nicotine and how nicotine produces addiction and influences smoking behavior provides a necessary basis for therapeutic advances in smoking cessation interventions. This chapter provides a review of several aspects of the human pharmacology of nicotine. These include the presence and levels of nicotine and related alkaloids in tobacco products, the absorption of nicotine from tobacco products and nicotine medications, the distribution of nicotine in body tissues, the metabolism and renal excretion of nicotine, nicotine and cotinine blood levels during tobacco use or nicotine replacement therapy, and biomarkers of nicotine exposure. For more details and references on the pharmacokinetics and metabolism of nicotine, the reader is referred to Hukkanen et al. (2005c). 

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). 

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