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Nicotine Chemistry, Metabolism, Kinetics and Biomarkers

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Part of the Handbook of Experimental Pharmacology book series (HEP,volume 192)

Abstract

Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransfease (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml−1. This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.

Keywords

  • Nicotine Replacement Therapy
  • Grapefruit Juice
  • Environmental Tobacco Smoke Exposure
  • Nicotine Concentration
  • Nicotine Intake

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  • 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

    PubMed  CAS  Google Scholar 

  • Armitage A, Dollery C, Houseman T, Kohner E, Lewis PJ, Turner D (1978) Absorption of nicotine from small cigars. Clin Pharmacol Ther 23(2):143–151

    PubMed  CAS  Google Scholar 

  • Armstrong DW, Wang X, Ercal N (1998) Enantiomeric composition of nicotine in smokeless tobacco, medicinal products, and commercial reagents. Chirality 10:587–591

    CAS  Google Scholar 

  • Asimus S, Hai TN, Van Huong N, Ashton M (2008) Artemisin and CYP2A6 activity in healthy subjects. Eur J Clin Pharmacol 64:283–292

    PubMed  CAS  Google Scholar 

  • Bendayan R, Sullivan JT, Shaw C, Frecker RC, Sellers EM (1990) Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans. Eur J Clin Pharmacol 38(2):165–169

    PubMed  CAS  Google Scholar 

  • Benowitz NL (1990) Clinical pharmacology of inhaled drugs of abuse: implications in understanding nicotine dependence. NIDA Res Monogr 99:12–29

    PubMed  CAS  Google Scholar 

  • Benowitz NL (1996) Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 18(2):188–204

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd (1984) Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35(4):499–504

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd (1985) Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J Pharmacol Exp Ther 234(1):153–155

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd (1993) Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin Pharmacol Ther 53(3):316–323

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd (1994) Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 56(5):483–493

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd (2000) Effects of cigarette smoking and carbon monoxide on nicotine and cotinine metabolism. Clin Pharmacol Ther 67(6):653–659

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd (2001) Trans-3′-hydroxycotinine: disposition kinetics, effects and plasma levels during cigarette smoking. Br J Clin Pharmacol 51(1):53–59

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd, Jones RT, Rosenberg J (1982a) Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther 221(2):368–372

    CAS  Google Scholar 

  • Benowitz NL, Kuyt F, Jacob P 3rd (1982b) Circadian blood nicotine concentrations during cigarette smoking. Clin Pharmacol Ther 32(6):758–764

    CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd, Savanapridi C (1987) Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin Pharmacol Ther 41(4):467–473

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Porchet H, Sheiner L, Jacob P 3rd (1988) Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther 44(1):23–28

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd, Fong I, Gupta S (1994) Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268(1):296–303

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Perez-Stable EJ, Fong I, Modin G, Herrera B, Jacob P 3rd (1999) Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 291(3):1196–1203

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Jacob P 3rd, Ahijevych K, Jarvis MJ, Hall S, LeHouezec J, Hansson A, Lichtenstein E, Henningfield J, Tsoh J, Hurt RD, Velicer W (2002a) Biochemical verification of tobacco use and cessation. Nicotine and Tobacco Research 4:149–159

    Google Scholar 

  • Benowitz NL, Perez-Stable EJ, Herrera B, Jacob P 3rd (2002b) Slower metabolism and reduced intake of nicotine from cigarette smoking in Chinese-Americans. J Natl Cancer Inst 94(2):108–115

    Google Scholar 

  • Benowitz NL, Herrera B, Jacob P, 3rd (2004) Mentholated cigarette smoking inhibits nicotine metabolism. J Pharmacol Exp Ther 310:1208–1215

    PubMed  CAS  Google Scholar 

  • Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd (2006) Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 79(5):480–488

    PubMed  CAS  Google Scholar 

  • Benowitz N, Bernert JT, Caraballo RS, Holiday DB, Wang J (2008a) Optimal Serum Cotinine Levels to Distinguish Cigarette Smokers and Non-Smokers within Different Racial/Ethnic Groups in the United States Between 1999–2004. Am J Epidemiol (in press)

    Google Scholar 

  • Benowitz N, Lessov-Schlaggar C, Swan G (2008b) Genetic Influences in the Variation in Renal Clearance of Nicotine and Cotinine. Clin Pharmacol Ther 84(2):243–247

    CAS  Google Scholar 

  • Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282(1):7–13

    PubMed  CAS  Google Scholar 

  • Byrd GD, Chang KM, Greene JM, deBethizy JD (1992) Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans-3′-hydroxycotinine in smokers. Drug Metab Dispos 20(2):192–197

    PubMed  CAS  Google Scholar 

  • Byrd GD, Uhrig MS, deBethizy JD, Caldwell WS, Crooks PA, Ravard A, Riggs R (1994) Direct determination of cotinine-N-glucuronide in urine using thermospray liquid chromatography/mass spectrometry. Biol Mass Spectrom 23(2):103–107

    PubMed  CAS  Google Scholar 

  • Caraballo RS, Giovino GA, Pechacek TF, Mowery PD, Richter PA, Strauss WJ, Sharp DJ, Eriksen MP, Pirkle JL, Maurer KR (1998) Racial and ethnic differences in serum cotinine levels of cigarette smokers: Third National Health and Nutrition Examination Survey, 1988–1991. JAMA 280(2):135–139

    PubMed  CAS  Google Scholar 

  • Cashman JR, Park SB, Yang ZC, Wrighton SA, Jacob P, 3rd, Benowitz NL (1992) Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N′-oxide. Chem Res Toxicol 5(5):639–646

    PubMed  CAS  Google Scholar 

  • Choi JH, Dresler CM, Norton MR, Strahs KR (2003) Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 5(5):635–644

    PubMed  CAS  Google Scholar 

  • Collier AM, Goldstein GM, Shrewsbury RP, Davis SM, Koch GG, Zhang C-A, Benowitz NL, Lewtas J, Williams RW (1994) Cotinine elimination and its use as a biomarker in young children involuntarily exposed to environmental tobacco smoke. Indoor Environ 3:353–359

    Google Scholar 

  • Crawford EL, Weaver DA, DeMuth JP, Jackson CM, Khuder SA, Frampton MW, Utell MJ, Thilly WG, Willey JC (1998) Measurement of cytochrome P450 2A6 and 2E1 gene expression in primary human bronchial epithelial cells. Carcinogenesis 19(10):1867–1871

    PubMed  CAS  Google Scholar 

  • Dahlstrom A, Lundell B, Curvall M, Thapper L (1990) Nicotine and cotinine concentrations in the nursing mother and her infant. Acta Paediatr Scand 79(2):142–147

    PubMed  CAS  Google Scholar 

  • de Leon J, Diaz FJ, Rogers T, Browne D, Dinsmore L, Ghosheh OH, Dwoskin LP, Crooks PA (2002) Total cotinine in plasma: a stable biomarker for exposure to tobacco smoke. J Clin Psychopharmacol 22(5):496–501

    PubMed  Google Scholar 

  • Dehn DL, Claffey DJ, Duncan MW, Ruth JA (2001) Nicotine and cotinine adducts of a melanin intermediate demonstrated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Chem Res Toxicol 14(3):275–279

    PubMed  CAS  Google Scholar 

  • Dempsey DA, Benowitz NL (2001) Risks and benefits of nicotine to aid smoking cessation in pregnancy. Drug Saf 24(4):277–322

    PubMed  CAS  Google Scholar 

  • Dempsey D, Jacob P, 3rd, Benowitz NL (2000) Nicotine metabolism and elimination kinetics in newborns. Clin Pharmacol Ther 67(5):458–465

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Fant RV, Henningfield JE, Shiffman S, Strahs KR, Reitberg DP (2000) A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches. Pharmacol Biochem Behav 67(3):479–482

    PubMed  CAS  Google Scholar 

  • Florescu A, Ferrence R, Einarson TR, Selby P, Kramer M, Woodruff S, Grossman L, Rankin A, Jacqz-Aigrain E, Koren G (2007) Reference values for hair cotinine as a biomarker of active and passive smoking in women of reproductive age, pregnant women, children, and neonates: systematic review and meta-analysis. Ther Drug Monit 29(4):437–446

    PubMed  CAS  Google Scholar 

  • Giovino G, Sidney S, Gfroerer J, O'Malley P, Allen J, Richter P, Ph DK (2004) Epidemiology of menthol cigarette use. Nicotine Tob Res 6(Suppl 1):S67–81

    PubMed  CAS  Google Scholar 

  • Gori GB, Benowitz NL, Lynch CJ (1986) Mouth versus deep airways absorption of nicotine in cigarette smokers. Pharmacol Biochem Behav 25(6):1181–1184

    PubMed  CAS  Google Scholar 

  • Gourlay SG, Benowitz NL (1996) The benefits of stopping smoking and the role of nicotine replacement therapy in older patients. Drugs Aging 9(1):8–23

    PubMed  CAS  Google Scholar 

  • Gourlay SG, Benowitz NL (1997) Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine. Clin Pharmacol Ther 62(4):453–463

    PubMed  CAS  Google Scholar 

  • Gow PJ, Ghabrial H, Smallwood RA, Morgan DJ, Ching MS (2001) Neonatal hepatic drug elimination. Pharmacol Toxicol 88(1):3–15

    PubMed  CAS  Google Scholar 

  • Gries JM, Benowitz N, Verotta D (1996) Chronopharmacokinetics of nicotine. Clin Pharmacol Ther 60(4):385–395

    PubMed  CAS  Google Scholar 

  • Guthrie SK, Zubieta JK, Ohl L, Ni L, Koeppe RA, Minoshima S, Domino EF (1999) Arterial/venous plasma nicotine concentrations following nicotine nasal spray. Eur J Clin Pharmacol 55(9):639–643

    PubMed  CAS  Google Scholar 

  • Hatsukami DK, Hecht SS, Hennrikus DJ, Joseph AM, Pentel PR (2003) Biomarkers of tobacco exposure or harm: application to clinical and epidemiological studies. 25–26 October 2001, Minneapolis, Minnesota. Nicotine Tob Res 5(3):387–396

    PubMed  CAS  Google Scholar 

  • Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3(10):733–744

    PubMed  CAS  Google Scholar 

  • Hecht SS, Carmella SG, Chen M, Dor Koch JF, Miller AT, Murphy SE, Jensen JA, Zimmerman CL, Hatsukami DK (1999a) Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation. Cancer Res 59(3):590–596

    CAS  Google Scholar 

  • Hecht SS, Carmella SG, Murphy SE (1999b) Effects of watercress consumption on urinary metabolites of nicotine in smokers. Cancer Epidemiol Biomarkers Prev 8(10):907–913

    CAS  Google Scholar 

  • Hecht SS, Hochalter JB, Villalta PW, Murphy SE (2000) 2′-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: formation of a lung carcinogen precursor. Proc Natl Acad Sci USA 97(23):12493–12497

    PubMed  CAS  Google Scholar 

  • Henningfield JE, Keenan RM (1993) Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 61(5):743–750

    PubMed  CAS  Google Scholar 

  • Henningfield JE, Stapleton JM, Benowitz NL, Grayson RF, London ED (1993) Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug Alcohol Depend 33(1):23–29

    PubMed  CAS  Google Scholar 

  • Higashi E, Fukami T, Itoh M, Kyo S, Inoue M, Yokoi T, Nakajima M (2007) Human CYP2A6 is induced by estrogen via estrogen receptor. Drug Metab Dispos 35:1935–1941

    PubMed  CAS  Google Scholar 

  • Hukkanen J, Vaisanen T, Lassila A, Piipari R, Anttila S, Pelkonen O, Raunio H, Hakkola J (2003) Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther 304(2):745–752

    PubMed  CAS  Google Scholar 

  • Hukkanen J, Dempsey D, Jacob P, 3rd, Benowitz NL (2005a) Effect of pregnancy on a measure of FMO3 activity. Br J Clin Pharmacol 60(2):224–226

    CAS  Google Scholar 

  • Hukkanen J, Gourlay SG, Kenkare S, Benowitz NL (2005b) Influence of menstrual cycle on cytochrome P450 2A6 activity and cardiovascular effects of nicotine. Clin Pharmacol Ther 77(3):159–169

    CAS  Google Scholar 

  • Hukkanen J, Jacob P 3rd, Benowitz NL (2005c) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57(1):79–115

    CAS  Google Scholar 

  • Hukkanen J, Jacob P 3rd, Benowitz NL (2006) Effect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearance. Clin Pharmacol Ther 80(5):522–530

    PubMed  CAS  Google Scholar 

  • Hurt RD, Dale LC, Fredrickson PA, Caldwell CC, Lee GA, Offord KP, Lauger GG, Marusic Z, Neese LW, Lundberg TG (1994) Nicotine patch therapy for smoking cessation combined with physician advice and nurse follow-up. One-year outcome and percentage of nicotine replacement. JAMA 271(8):595–600

    PubMed  CAS  Google Scholar 

  • Jacob P, 3rd, Benowitz NL (1991) Oxidative metabolism of nicotine in vivo. In: F. Adlkofer, K. Thurau (eds) Effects of nicotine on biological systems. Birkhauser Verlag, Basel, pp 35–44

    Google Scholar 

  • Jacob P, 3rd, Shulgin AT, Benowitz NL (1990) Synthesis of (3′R, 5′S)-trans-3′-hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3′-hydroxycotinine in humans is highly stereoselective. J Med Chem 33(7):1888–1891

    PubMed  CAS  Google Scholar 

  • Jacob P, 3rd, Yu L, Shulgin AT, Benowitz NL (1999) Minor tobacco alkaloids as biomarkers for tobacco use: comparison of users of cigarettes, smokeless tobacco, cigars, and pipes. Am J Public Health 89(5):731–736

    PubMed  Google Scholar 

  • Jacob P, 3rd, Hatsukami D, Severson H, Hall S, Yu L, Benowitz NL (2002) Anabasine and anatabine as biomarkers for tobacco use during nicotine replacement therapy. Cancer Epidemiol Biomarkers Prev 11(12):1668–1673

    PubMed  CAS  Google Scholar 

  • Jarvis MJ, Boreham R, Primatesta P, Feyerabend C, Bryant A (2001) Nicotine yield from machinesmoked cigarettes and nicotine intakes in smokers: evidence from a representative population survey. J Natl Cancer Inst 93(2):134–138

    PubMed  CAS  Google Scholar 

  • Johansson CJ, Olsson P, Bende M, Carlsson T, Gunnarsson PO (1991) Absolute bioavailability of nicotine applied to different nasal regions. Eur J Clin Pharmacol 41(6):585–588

    PubMed  CAS  Google Scholar 

  • Johnstone E, Benowitz N, Cargill A, Jacob R, Hinks L, Day I, Murphy M, Walton R (2006) Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clin Pharmacol Ther 80(4):319–330

    PubMed  CAS  Google Scholar 

  • Kandel DB, Hu MC, Schaffran C, Udry JR, Benowitz NL (2007) Urine nicotine metabolites and smoking behavior in a multiracial/multiethnic national sample of young adults. Am J Epidemiol 165(8):901–910

    PubMed  Google Scholar 

  • Kozlowski LT, Mehta NY, Sweeney CT, Schwartz SS, Vogler GP, Jarvis MJ, West RJ (1998) Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the United Kingdom, and the United States. Tob Control 7(4):369–375

    PubMed  CAS  Google Scholar 

  • Krul C, Hageman G (1998) Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 709(1):27–34

    PubMed  CAS  Google Scholar 

  • Kyerematen GA, Morgan M, Warner G, Martin LF, Vesell ES (1990) Metabolism of nicotine by hepatocytes. Biochem Pharmacol 40(8):1747–1756

    PubMed  CAS  Google Scholar 

  • Le Gal A, Dreano Y, Lucas D, Berthou F (2003) Diversity of selective environmental substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine, and N-nitrosobenzylmethylamine. Toxicol Lett 144(1):77–91

    PubMed  CAS  Google Scholar 

  • Lee BL, Benowitz NL, Jacob P 3rd (1987) Influence of tobacco abstinence on the disposition kinetics and effects of nicotine. Clin Pharmacol Ther 41(4):474–479

    PubMed  CAS  Google Scholar 

  • Lee BL, Jacob P 3rd, Jarvik ME, Benowitz NL (1989) Food and nicotine metabolism. Pharmacol Biochem Behav 33(3):621–625

    PubMed  CAS  Google Scholar 

  • Leete E (1983) Biosynthesis and metabolism of the tobacco alkaloids. In: Pelletier SW (ed) Alkaloids: chemical and biological perspectives. Wiley, New York, pp 85–152

    Google Scholar 

  • Leong JW, Dore ND, Shelley K, Holt EJ, Laing IA, Palmer LJ, LeSouef PN (1998) The elimination half-life of urinary cotinine in children of tobacco-smoking mothers. Pulm Pharmacol Ther 11(4):287–290

    PubMed  CAS  Google Scholar 

  • Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A, Benowitz N (2006) Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol Ther 79(6):600–608

    PubMed  CAS  Google Scholar 

  • Lindell G, Lunell E, Graffner H (1996) Transdermally administered nicotine accumulates in gastric juice. Eur J Clin Pharmacol 51(3–4):315–318

    PubMed  CAS  Google Scholar 

  • Liston HL, Markowitz JS, DeVane CL (2001) Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21(5):500–515

    PubMed  CAS  Google Scholar 

  • Lunell E, Molander L, Ekberg K, Wahren J (2000) Site of nicotine absorption from a vapour inhaler-comparison with cigarette smoking. Eur J Clin Pharmacol 55(10):737–741

    PubMed  CAS  Google Scholar 

  • MacDougall JM, Fandrick K, Zhang X, Serafin SV, Cashman JR (2003) Inhibition of human liver microsomal (S)-nicotine oxidation by (–)-menthol and analogues. Chem Res Toxicol 16(8):988–993

    PubMed  CAS  Google Scholar 

  • Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P, Jr., Koch P, Antonian L, Wagner G, Yu L, Parkinson A (2003) Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 31(4):421–431

    PubMed  CAS  Google Scholar 

  • McBride JS, Altman DG, Klein M, White W (1998) Green tobacco sickness. Tob Control 7(3):294–298

    PubMed  CAS  Google Scholar 

  • McCusker K, McNabb E, Bone R (1982) Plasma nicotine levels in pipe smokers. JAMA 248(5):577–578

    PubMed  CAS  Google Scholar 

  • McKennis H, Jr., Turnbull LB, Bowman ER, Tamaki E (1963) The synthesis of hydroxycotinine and studies on its structure. J Org Chem 28:383–387

    CAS  Google Scholar 

  • McNabb ME (1984) Chewing nicotine gum for 3 months: what happens to plasma nicotine levels? Can Med Assoc J 131(6)589–592

    PubMed  CAS  Google Scholar 

  • McNabb ME, Ebert RV, McCusker K (1982) Plasma nicotine levels produced by chewing nicotine gum. JAMA 248(7):865–868

    PubMed  CAS  Google Scholar 

  • Messina ES, Tyndale RF, Sellers EM (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 282(3):1608–1614

    PubMed  CAS  Google Scholar 

  • Meunier V, Bourrie M, Julian B, Marti E, Guillou F, Berger Y, Fabre G (2000) Expression and induction of CYP1A1/1A2, CYP2A6 and CYP3A4 in primary cultures of human hepatocytes: a 10-year follow-up. Xenobiotica 30(6)589–607

    PubMed  CAS  Google Scholar 

  • Molander L, Lunell E, Andersson SB, Kuylenstierna F (1996) Dose released and absolute bioavailability of nicotine from a nicotine vapor inhaler. Clin Pharmacol Ther 59(4):394–400

    PubMed  CAS  Google Scholar 

  • Molander L, Hansson A, Lunell E, Alainentalo L, Hoffmann M, Larsson R (2000) Pharmacokinetics of nicotine in kidney failure. Clin Pharmacol Ther 68(3):250–260

    PubMed  CAS  Google Scholar 

  • Molander L, Hansson A, Lunell E (2001) Pharmacokinetics of nicotine in healthy elderly people. Clin Pharmacol Ther 69(1):57–65

    PubMed  CAS  Google Scholar 

  • Munzel PA, Schmohl S, Heel H, Kalberer K, Bock-Hennig BS, Bock KW (1999) Induction of human UDP glucuronosyltransferases (UGT1A6, UGT1A9, and UGT2B7) by tbutylhydroquinone and 2,3,7,8-tetrachlorodibenzo-p-dioxin in Caco-2 cells. Drug Metab Dispos 27(5):569–573

    PubMed  CAS  Google Scholar 

  • Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K, Funae Y, Shimada N, Kamataki T, Kuroiwa Y (1996) Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos 24(11):1212–1217

    PubMed  CAS  Google Scholar 

  • Neurath GB (1994) Aspects of the oxidative metabolism of nicotine. Clin Investig 72(3):190–195

    PubMed  CAS  Google Scholar 

  • Neurath GB, Dunger M, Orth D, Pein FG (1987) Trans-3′-hydroxycotinine as a main metabolite in urine of smokers. Int Arch Occup Environ Health 59(2):199–201

    PubMed  CAS  Google Scholar 

  • Neurath GB, Orth D, Pein FG (1991) Detection of nornicotine in human urine after infusion of nicotine. In: Adlkofer F, Thurau K (eds) Effects of nicotine on biological systems. Birkhauser Verlag, Basel, pp 45–49

    Google Scholar 

  • Nolin TD, Frye RF, Matzke GR (2003) Hepatic drug metabolism and transport in patients with kidney disease. Am J Kidney Dis 42(5):906–925

    PubMed  CAS  Google Scholar 

  • Obach RS (2004) Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab Dispos 32(1):89–97

    PubMed  CAS  Google Scholar 

  • Pankow JF (2001) A consideration of the role of gas/particle partitioning in the deposition of nicotine and other tobacco smoke compounds in the respiratory tract. Chem Res Toxicol 14(11):1465–1481

    PubMed  CAS  Google Scholar 

  • Park SB, Jacob P, 3rd, Benowitz NL, Cashman JR (1993) Stereoselective metabolism of (S)-(-)-nicotine in humans: formation of trans-(S)-(-)-nicotine N-1′-oxide. Chem Res Toxicol 6(6):880–888

    PubMed  CAS  Google Scholar 

  • Patterson F, Benowitz N, Shields P, Kaufmann V, Jepson C, Wileyto P, Kucharski S, Lerman C (2003) Individual differences in nicotine intake per cigarette. Cancer Epidemiol Biomarkers Prev 12(5):468–471

    PubMed  CAS  Google Scholar 

  • Patterson F, Schnoll R, Wileyto E, Pinto A, Epstein L, Shields P, Hawk L, Tyndale R, Benowitz N, Lerman C (2008) Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo-controlled Trial of Bupropion. Clin Pharmacol Ther 84(3):320–325

    PubMed  CAS  Google Scholar 

  • Perez-Stable EJ, Herrera B, Jacob P 3rd, Benowitz NL (1998) Nicotine metabolism and intake in black and white smokers. JAMA 280(2):152–156

    PubMed  CAS  Google Scholar 

  • Perry RJ, Griffiths W, Dextraze P, Solomon RJ, Trebbin WM (1984) Elevated nicotine levels in patients undergoing hemodialysis. A role in cardiovascular mortality and morbidity? Am J Med 76(2):241–246

    PubMed  CAS  Google Scholar 

  • Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289(3):1545–1552

    PubMed  CAS  Google Scholar 

  • Rae JM, Johnson MD, Lippman ME, Flockhart DA (2001) Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther 299(3):849–857

    PubMed  CAS  Google Scholar 

  • Rebagliato M, Bolumar F, Florey Cdu V, Jarvis MJ, Perez-Hoyos S, Hernandez-Aguado I, Avino MJ (1998) Variations in cotinine levels in smokers during and after pregnancy. Am J Obstet Gynecol 178(3):568–571

    PubMed  CAS  Google Scholar 

  • Ren Q, Murphy SE, Zheng Z, Lazarus P (2000) O-Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanol (NNAL) by human UDP-glucuronosyltransferases 2B7 and 1A9. Drug Metab Dispos 28(11):1352–1360

    PubMed  CAS  Google Scholar 

  • Rose JE, Behm FM, Westman EC, Coleman RE (1999) Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction. Drug Alcohol Depend 56(2):99–107

    PubMed  CAS  Google Scholar 

  • Runkel M, Bourian M, Tegtmeier M, Legrum W (1997) The character of inhibition of the metabolism of 1,2-benzopyrone (coumarin) by grapefruit juice in human. Eur J Clin Pharmacol 53(3–4):265–269

    PubMed  CAS  Google Scholar 

  • Schneider NG, Olmstead R, Mody FV, Doan K, Franzon M, Jarvik ME, Steinberg C (1995) Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial. Addiction 90(12):1671–1682

    PubMed  CAS  Google Scholar 

  • Schneider NG, Olmstead RE, Franzon MA, Lunell E (2001) The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 40(9):661–684

    PubMed  CAS  Google Scholar 

  • Schoedel KA, Sellers EM, Palmour R, Tyndale RF (2003) Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration. Mol Pharmacol 63(1):96–104

    PubMed  CAS  Google Scholar 

  • Selby P, Hackman R, Kapur B, Klein J, Koren G (2001) Heavily smoking women who cannot quit in pregnancy: evidence of pharmacokinetic predisposition. Ther Drug Monit 23(3):189–191

    PubMed  CAS  Google Scholar 

  • Sellers EM, Kaplan HL, Tyndale RF (2000) Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking. Clin Pharmacol Ther 68(1):35–43

    PubMed  CAS  Google Scholar 

  • Sellers EM, Ramamoorthy Y, Zeman MV, Djordjevic MV, Tyndale RF (2003) The effect of methoxsalen on nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in vivo. Nicotine Tob Res 5(6):891–899

    PubMed  CAS  Google Scholar 

  • Shigenaga MK, Trevor AJ, Castagnoli N Jr (1988) Metabolism-dependent covalent binding of (S)-[5-3H]nicotine to liver and lung microsomal macromolecules. Drug Metab Dispos 16(3):397–402

    PubMed  CAS  Google Scholar 

  • Siegmund B, Leitner E, Pfannhauser W (1999) Determination of the nicotine content of various edible nightshades (Solanaceae) and their products and estimation of the associated dietary nicotine intake. J Agric Food Chem 47(8):3113–3120

    PubMed  CAS  Google Scholar 

  • Stepanov I, Hecht SS, Lindgren B, Jacob P 3rd, Wilson M, Benowitz NL (2007) Relationship of human toenail nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol to levels of these biomarkers in plasma and urine. Cancer Epidemiol Biomarkers Prev 16(7):1382–1386

    PubMed  CAS  Google Scholar 

  • Swan GE, Benowitz NL, Lessov CN, Jacob P, 3rd, Tyndale RF, Wilhelmsen K (2005) Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 15(2):115–125

    PubMed  CAS  Google Scholar 

  • Taavitsainen P, Juvonen R, Pelkonen O (2001) In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene. Drug Metab Dispos 29(3):217–222

    PubMed  CAS  Google Scholar 

  • Takami K, Saito H, Okuda M, Takano M, Inui KI (1998) Distinct characteristics of transcellular transport between nicotine and tetraethylammonium in LLC-PK1 cells. J Pharmacol Exp Ther 286(2):676–680

    PubMed  CAS  Google Scholar 

  • Tateishi T, Nakura H, Asoh M, Watanabe M, Tanaka M, Kumai T, Takashima S, Imaoka S, Funae Y, Yabusaki Y, Kamataki T, Kobayashi S (1997) A comparison of hepatic cytochrome P450 protein expression between infancy and postinfancy. Life Sci 61(26):2567–2574

    PubMed  CAS  Google Scholar 

  • Tyndale RF, Sellers EM (2001) Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk. Drug Metab Dispos 29(4 Pt 2):548–552

    PubMed  CAS  Google Scholar 

  • Tyroller S, Zwickenpflug W, Richter E (2002) New sources of dietary myosmine uptake from cereals, fruits, vegetables, and milk. J Agric Food Chem 50(17):4909–4915

    PubMed  CAS  Google Scholar 

  • Urakami Y, Okuda M, Maasuda S, Saito H, Inui KI (1998) Functional characteristics and membrane locatlization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Ther 287:800–805

    CAS  Google Scholar 

  • USDHHS (2001) Risks associated with smoking cigarettes with low machine-measured yields of tar and nicotine. Smoking and Tobacco Control Monographs, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute

    Google Scholar 

  • Voncken P, Rustemeier K, Schepers G (1990) Identification of cis-3′-hydroxycotinine as a urinary nicotine metabolite. Xenobiotica 20(12):1353–1356

    PubMed  CAS  Google Scholar 

  • Wagenknecht LE, Cutter GR, Haley NJ, Sidney S, Manolio TA, Hughes GH, Jacobs DR (1990) Racial differences in serum cotinine levels among smokers in the coronary artery risk development in (young) adults study. Am J Public Health 80(9):1053–1056

    PubMed  CAS  Google Scholar 

  • Wald NJ, Idle M, Boreham J, Bailey A (1981) Serum cotinine levels in pipe smokers: evidence against nicotine as cause of coronary heart disease. Lancet 2(8250):775–777

    PubMed  CAS  Google Scholar 

  • Wald NJ, Idle M, Boreham J, Bailey A, Van Vunakis H (1984) Urinary nicotine concentrations in cigarette and pipe smokers. Thorax 39(5):365–368

    PubMed  CAS  Google Scholar 

  • West R, Hajek P, Foulds J, Nilsson F, May S, Meadows A (2000) A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. Psychopharmacology (Berl) 149(3):198–202

    CAS  Google Scholar 

  • Xia XY, Peng RX, Yu JP, Wang H, Wang J (2002) In vitro metabolic characteristics of cytochrome P-450 2A6 in Chinese liver microsomes. Acta Pharmacol Sin 23(5):471–476

    PubMed  CAS  Google Scholar 

  • Zevin S, Benowitz NL (1999) Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 36(6):425–438

    PubMed  CAS  Google Scholar 

  • Zevin S, Jacob P 3rd, Benowitz N (1997) Cotinine effects on nicotine metabolism. Clin Pharmacol Ther 61(6):649–654

    PubMed  CAS  Google Scholar 

  • Zevin S, Schaner ME, Giacomini KM (1998) Nicotine transport in a human choriocarcinoma cell line (JAR). J Pharm Sci 87:702–706

    PubMed  CAS  Google Scholar 

  • Zevin S, Jacob P 3rd, Benowitz NL (2000) Nicotine-mecamylamine interactions. Clin Pharmacol Ther 68(1):58–66

    PubMed  CAS  Google Scholar 

  • Zhang W, Kilicarslan T, Tyndale RF, Sellers EM (2001) Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab Dispos 29(6):897–902

    PubMed  CAS  Google Scholar 

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Benowitz, N.L., Hukkanen, J., Jacob, P. (2009). Nicotine Chemistry, Metabolism, Kinetics and Biomarkers. In: Henningfield, J.E., London, E.D., Pogun, S. (eds) Nicotine Psychopharmacology. Handbook of Experimental Pharmacology, vol 192. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-69248-5_2

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