Nicotine and metabolites

Quantitative aspects of the pattern of nicotine metabolism have been elucidated fairly well in people (Fig. 4). Approximately 90% of a systemic dose of nicotine can be accounted for as nicotine and metabolites in urine (Benowitz et al. 1994). Based on studies with simultaneous infusion of labeled nicotine and cotinine, it has been determined that 70-80% of nicotine is converted to cotinine (Benowitz and Jacob 1994). About 4-7% of nicotine is excreted as nicotine N -oxide and 3-5% as nicotine glucuronide (Benowitz et al. 1994 Byrd et al. 1992). Cotinine is excreted unchanged in urine to a small degree (10-15% of the nicotine and metabolites in urine). The remainder is converted to metabolites, primarily fra i -3 -hydroxycotinine (33 0%), cotinine glucuronide (12-17%), and trans-3 -hydroxycotinine glucuronide (7-9%). 

A series of reviews describing nicotine metabolism has recently appeared [2], Specific topics covered include the biosynthesis and metabolism of nicotine and related alkaloids [3], an overview of mammalian nicotine metabolism [4], the role of cytochrome P450 in nicotine metabolism [5], nicotine metabolism beyond cotinine [6], N-oxidation, A -methylation, and N-conjugation reactions of nicotine [7], extrahepatic metabolism of nicotine and related compounds [8], metabolism of the minor tobacco alkaloids [9], analysis and levels of nicotine and metabolites in body fluids [10], kinetics of nicotine and its metabolites in animals [11], pharmacokinetics of (S)-nicotine and metabolites in humans [12], and sources of inter-individual variation in nicotine pharmacokinetics [13]. Another recent review described variables which affect nicotine metabolism [14]. Several compilations of studies or reviews on the tobacco-specific A-nitrosamines are available [15-18]... 

None or minimal "direct injection" Ease, speed, cost, potential for automation Rarely feasible, requires relatively clean matrix (i.e., urine) and analyte that requires no preconcentration, may still require filtration or centrifugation to clarify sample Urine nicotine and metabolites by LC-MS/MS [1]... 

FIGURE 4.8 Structures of the CYP2A6 substrates, coumarin and nicotine, and their metabolites. 

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. 

Dempsey D, Jacob P, 3rd, Benowitz NL (2002) Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 301(2) 594-598 Dempsey D, Tutka P, Jacob P, 3rd, Allen F, Schoedel K, Tyndale RF, Benowitz NL (2004) Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 76 64-72... 

Denton TT, Zhang X, Cashman JR (2004) Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6. Biochem Pharmacol 67(4) 751-756 English PB, Eskenazi B, Christianson RE (1994) Black-white differences in serum cotinine levels among pregnant women and subsequent effects on infant birthweight. Am J Public Health 84(9) 1439-1443... 

Kyerematen GA, Taylor LH, deBethizy JD, Vesell ES (1988a) Pharmacokinetics of nicotine and 12 metabolites in the rat. Application of a new radiometric high performance liquid chromatography assay. Drug Metab Dispos 16 125-129... 

Increased hypothalamic NE levels and utilization Reduced NAcc DA output/increased clearance Abolished effect of nicotine on limbic DA metabolism Decreased DA output and metabolites in NAcc (not in frontal cortex)... 

Domino EF (1999) Pharmacological significance of nicotine. In Gorrod JW, Jacob P (eds) Analytical determination of nicotine and related compounds and their metabolites. Elsevier, Amsterdam, pp 1-11... 

Kronstrand et al. [48] developed an HPLC-MS-MS method able to screen simultaneously for opiates, cocaine, amphetamines, nicotine, and the metabolite cotinine, and selected benzodiazepines in hair. 

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 seconds, 66 to 77% of the nicotine in the smoke will be absorbed across the oral mucosa. If tobacco smoke is inhaled, approximately 90 to 98% of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to 90% of the alkaloid. The kidney rapidly eliminates nicotine and its metabolites. 

There are other small biomolecules, specific to certain types of cells or organisms. For example, vascular plants contain, in addition to the universal set, small molecules called secondary metabolites, which play a role specific to plant life. These metabolites include compounds that give plants their characteristic scents, and compounds such as morphine, quinine, nicotine, and caffeine that are valued for their physiological effects on humans but used for other purposes by plants. The entire collection of small molecules in a given cell has been called that cell s metabolome, in parallel with the term genome (defined earlier and expanded on in... 

Denton TT, Zhang X, Cashman JR. Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6. Biochem Pharmacol 2004 67(4) 751-756. 

The 13C n.m.r. spectra of nicotine metabolites have been measured and discussed.39 The stereoselectivity of the iodomethylation of nicotine and seven analogues has been studied with the aid of 13C n.m.r. spectroscopy.40 Nicotine yields 2-methylnicotine as the major product when treated with methyl-lithium or methyl radicals, accompanied, as reported earlier, by 4- and 6-methylnicotine. Nicotine tV-oxide and methylmagnesium bromide afford 2- and 6-methyl-nicotines.41 Anabaseine (26), a well-known minor alkaloid of tobacco, has been identified as a poison-gland product in ants of the genus Aphaenogaster, which use it as an attractant.42... 

Myosmine (3[2-pyrrolidinyl]pyridine) and nicotine (3[l-methyl-2-pyrrolidinyl]pyridine) (Section 1, Appendix) and a number of related bioactive alkaloids occur in Nkotiana tabacum (tobacco) (Solanaceae) and variously in other Solanaceae such as Duboisia species. Nicotine and the related tobacco compounds nicotyrine and (—)-nornicotine are agonists (neurotransmitter mimics ) of the so-called (nicotine binding) nACh-R involved in neurotransmission and in neuromuscular transmission for skeletal muscle. The extraordinary addictiveness of nicotine derives from nACh-R agonists causing dopamine release and activating the mesolimbic dopamine system yielding reward effects. The antidepressant (—)-cotinine is the major nicotine metabolite in humans and a nicotinic agonist. 

Yes. In situations where drugs are known to be present in the environment, it is easy to demonstrate that passive exposure can produce positive hair analysis results. In a study by Haley and Hoffmaim of the nicotine and cotinine concentrations in the hair of smokers and nonsmokers, there appeared to be a higher average of nicotine in the unwashed hair of smokers (average 8.75 ng/mg). However, nonsmokers also had an appreciable level of nicotine (average 2.42 ng/mg) which overlapped that of smokers. In contrast, cotinine (the nicotine metabolite) does appear to be a marker of tobacco use in this population. More recently, Kintz and co-workers and Kintz proposed a cutoff level of 2 ng of nicotine/mg of hair to ehminate nonsmoking individuals. Even at this level, some nonsmokers would be positive. 

Heavy smoking is very prevalent amongst file drug-dependent community, and the presence of nicotine and its metabolites in the basic extract can confuse the interpretation of the TEC plates. In System TA, nicotine and its metabolites coalesce with an Rf... 

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