Nicotine metabolite ratio

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... 

Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A, Benowitz N (2006) Nicotine metabolite ratio predicts efiScacy of transdermal nicotine for smoking cessation, Clin Pharmacol Ther79(6) 600-608... 

Lewis, D.F. and J.W, Gorrod (2002). Molecular orbital calculations and nicotine metabolism A rationale for experimentally observed metabolite ratios. Drug Metabol. Drug Interact. 19, 29-39. 

The most generally interesting intracellular metabolites are the adenine nucleotide phosphates (ATP/ADP/AMP) and the nicotinic acid/adenine dinucleotide phosphates (NAD(P)H/NAD(P)). The pool concentrations and ratios of these can serve as markers for the physiological status of a culture. 

The results (Leete and Chedekel, 1974) indicate that 48% of [2- H](-)-nomicotine and 52% [2- C](+)-nomicotine is incorporated from the labeled nicotine. Thus if (+)-nornicotine is formed from (-)-nicotine, the transformation must involve the loss of the hydrogen from C-2 however, almost the same [ HA C]ratio occurs as in the administered mixture of [2 - H](-)-nicotine and [2 2- C](+)-nicotine, which indicates that in N. glauca (+)- and (-)-nicotine are demethylated at similar rates. If the demethylation had been stereospeciflc for (-)-nicotine, the resultant nomi-cotine would have its [ HA C]ratio doubled. This led the authors to propose a scheme for the formation of (+)-nicotine and (-)-nicotine (Figure 6.11). This mechanism accounts for the partial racemization of the nornicotine derived from (-)-nicotine a Cope elimination of nicotine N -oxide (a) would involve one of the hydrogens at C-3, which would provide the unsaturated compound (b). Elimination of water from this hydroxy amine yields the Schiff base (c), which upon hydrolysis yields formaldehyde or other Cl metabolite and the primary amine (d). Cyclization of this intermediate yields (+)- and ( )-nomicotine. Leete and Chedekel presume that these steps are enzyme mediated, and it is to be expected that the final cyclization would yield a preferential amount of (+)- or (-)-nornicotine however, the mechanism which yields (+)-nornicotine from (-)-nicotine remains unknown. 

Nicotinamide is present in pork, beef, chicken, and fish. 2-Py and 4-Py are the major metabolites of nicotinic acid and nicotinamide excreted in urine. The contents of 2-Py and 4-Py in blood are below the limit of detection (33). The HPLC methods for analysis of nicotinamide and the related compounds are summarized in Table 4. Shibata et al. (34) reported the simultaneous measurement of nicotinamide, 2-Py, and 4-Py. This method is commonly applicable not only to urine and pharmaceutical preparations but also biological materials and foods. Chromatograms of a reference mixture of isonicotinamide (used as an internal standard), nicotinamide, 2-Py, and 4-Py and of extracts of rat urine, human urine, rat liver, and of the extract of multivitamin preparations are shown in Figure 10. The detection limits for nicotinamide, 2-Py, and 4-Py were 4 pmol (552 pg), 10 pmol (1220 pg), and 2 pmol (304 pg), respectively, at a signal-to-noise ratio of 5 1. Daily urinary excretion of nicotinamide, 2-Py and 4-Py in rats, mice, guinea pigs, hamsters and humans is given in Table 5. 

Other urinary excretion products of niacin include nicotinuric acid (nicotinoyl glycine) nicotinamide N-oxide, and trigonelline (N -methyl nicotinic acid) the latter may arise from bacterial action in the gut or from the absorption of this substance from foods. The pattern of the different turnover metabolites varies between species, between diets (depending partly on the ratio of nicotinamide to nicotinic acid in the diet), and partly with niacin status thus there are complex regulatory mechanisms to be considered. 

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