Cotinine, tobacco

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). 

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. 

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. 

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). 

Neonates have diminished nicotine metabolism, as demonstrated by a nicotine half-life of three to four times longer in newborns exposed to tobacco smoke than in adnlts (Dempsey et al. 2000). Cotinine half-life is reported to be similar in neonates, older children, and adults in two studies (Dempsey et al. 2000 Leong et al. 1998). Other studies found that the half-life of urine cotinine was about three times longer in children less than one year old than to the cotinine half-life in adults (Collier et al. 1994). Urine cotinine half-life can be influenced by variations in urine volume and excretion of creatinine. The study by Dempsey et al. was the only one in which the half-life of cotinine was calculated based on both the blood and urine cotinine concentrations (Dempsey et al. 2000). In that study, both the blood and urine half-lives were similar to adult values, supporting the notion that neonates have the same cotinine half-life as older children and adults. 

These studies suggest that there are substance(s) in tobacco smoke, as yet unidentified, that inhibit the metabolism of nicotine. Because nicotine and cotinine are metabolized by the same enzyme, the possibility that cotinine might be responsible for the slowed metabolism of nicotine in smokers was examined. In a study in which nonsmokers received an intravenous infusion of nicotine with and without pretreatment with high doses of cotinine, there was no effect of cotinine on the clearance of nicotine (Zevin et al. 1997). Also, carbon monoxide at levels and in patterns similar to those experienced during smoking had no effect on nicotine and cotinine clearance (Benowitz and Jacob 2000). 

Nicotine and Cotinine Blood Levels During Tobacco Use and Nicotine Replacement Therapy... 

This section focnses on the nse of nicotine and cotinine and other tobacco alkaloids as biomarkers of tobacco exposure. Other potential biomarkers of exposure to the particulate or gas phase of tobacco smoke are described in the review papers cited above. 

In studies of smoking cessation, anatabine is recommended as nicotine replacement therapies will lead to the presence of nicotine and cotinine without any tobacco exposure... 

While cotinine functions fairly well as a marker of nicotine intake, it is not perfect due to individual variation in metalxtlism as discussed previously. As described earlier in this chapter, cotinine metabolism is affected by factors such as race, gender, age, genetic variation in the liver enzyme CYP2A6, and/or by the presence of pregnancy, liver or kidney disease. Another limitation to the use of cotinine is that, given an average half-life of 16 h, cotinine levels reflect relatively short-term exposure to tobacco (that is, over the past 3 days). 

The use of hair as a material in which to measure nicotine and cotinine has been proposed as a way to assess long-term exposure to nicotine from tobacco products. Nicotine and cotinine are incorporated into hair as it grows over time. The average rate of hair growth is 1 cm per month. Thus, measurements of levels of nicotine may provide a way of assessing exposure of a person to nicotine over several months (Al-Delaimy et al. 2002 Florescu et al. 2007). 

Potentials problems with the use of hair include a strong influence of hair pigmentation on nicotine and cotinine binding and uptake (Dehn et al. 2001). Nicotine and cotinine are bound to melanin. As a result, dark hair binds much more nicotine than does blond or white hair. This makes comparison across individuals difficult. Also, hair is exposed to nicotine and cotinine from sweat and from sebaceous gland secretions, and to nicotine from environmental tobacco smoke exposure. Washing the hair before analysis may reduce this problem of environmental contamination, but it is not likely to remove all environmental nicotine and cotiiune. 

Optimal Cotinine Cut-Points to Distinguish Tobacco Use From No Tobacco Use... 

Al-Delaimy WK, Crane J, Woodward A (2002) Is the hair nicotine level a more accurate biomarker of environmental tobacco smoke exposure than urine cotinine J Epidemiol Community Health 56(1) 66-71... 

Benowitz NL (1990) Chnical pharmacology of inhaled drags of abuse implications in understanding nicotine dependence. NIDA Res Monogr 99 12-29 Benowitz NL (1996) Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 18(2) 188-204... 

Leete E (1983) Biosynthesis and metabohsm of the tobacco alkaloids. In Pelletier SW (ed) Alkaloids chemical and biological perspectives, WUey, New York, pp 85-152 Leong JW, Dore ND, SheUey K, Holt EJ, Laing lA, Palmer LJ, LeSouef PN (1998) The elimination half-hfe of urinary cotinine in children of tobacco-smoking mothers, Pulm Pharmacol Ther ll(4) 287-290... 

The predominant alkaloid fonnd in tobacco is (—)-nicotine other molecnles found in tissnes of smokers are either present in tobacco smoke or are metabolites of nicotine, inclnding (4-)-nicotine, (-P)-nomicotine, (—)-nomicotine and (—)-cotinine, the major metabolite (Clark et al. 1965). In animals trained to recognise the stunnlns produced by (—)-nicotine, (-P)-nicotine fully substituted for (—)-nicotine but was about one-tenth as potent. There was no stereoselectivity in responding observed with the metabolite nomicotine and both (-p) and (—)-isomers fully substituted for nicotine but again were 10-fold less potent. (—)-Cotinine also substitnted for nicotine at very high doses bnt this conld be explained by the presence of small amounts of (—)-nicotine in the sample of cotinine (Goldberg et al. 1989). 

Saliva The use of saliva as a diagnostic fluid has been studied for many years [266]. While the ease and noninvasiveness with which a sample can be obtained make this matrix attractive to the medical community, the use of saliva to detect exposures of persons to environmental contaminants has not been investigated in many studies. However, it has been established that the measurement of cotinine, an indicator of exposure to environmental tobacco smoke, in saliva is correlated with concentrations of cotinine in serum [267]. 

A6 Coumarin, tobacco nitrosamines, nicotine (to cotinine and 2 -hydroxynicotine) Rifampin, phenobarbital Tranylcypromine, menthofuran, methoxsalen... 

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