Clinical Pharmacokinetics

, Volume 55, Issue 11, pp 1353–1368 | Cite as

Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products

  • Gail D. Anderson
  • Lingtak-Neander Chan
Review Article


Tobacco smoke contains a large number of compounds in the form of metals, volatile gases and insoluble particles, as well as nicotine, a highly addictive alkaloid. Marijuana is the most widely used illicit drug of abuse in the world, with a significant increase in the USA due to the increasing number of states that allow medical and recreational use. Of the over 70 phytocannabinoids in marijuana, Δ9-tetrahydrocannabinol (Δ9THC), cannabidiol (CBD) and cannibinol are the three main constituents. Both marijuana and tobacco smoking induce cytochrome P450 (CYP) 1A2 through activation of the aromatic hydrocarbon receptor, and the induction effect between the two products is additive. Smoking cessation is associated with rapid downregulation of CYP1A enzymes. On the basis of the estimated half-life of CYP1A2, dose reduction of CYP1A drugs may be necessary as early as the first few days after smoking cessation to prevent toxicity, especially for drugs with a narrow therapeutic index. Nicotine is a substrate of CYP2A6, which is induced by oestrogen, resulting in lower concentrations of nicotine in females than in males, especially in females taking oral contraceptives. The significant effects of CYP3A4 inducers and inhibitors on the pharmacokinetics of Δ9THC/CBD oromucosal spray suggest that CYP3A4 is the primary enzyme responsible for the metabolism of Δ9THC and CBD. Limited data also suggest that CBD may significantly inhibit CYP2C19. With the increasing use of marijuana and cannabis products, clinical studies are needed in order to determine the effects of other drugs on pharmacokinetics and pharmacodynamics.


Nicotine Smoking Cessation Clopidogrel Bupropion Ritonavir 
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.


Compliance with Ethical Standards

No sources of funding were used in the preparation of this review. Gail D. Anderson and Lingtak-Neander Chan have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    World Health Organization (WHO). Global health observatory data: prevalence of tobacco use. Geneva: World Health Organization; 2015. Available from: Accessed 20 Nov 2015.
  2. 2.
    Centers for Disease Control and Prevention. Current cigarette smoking among adults—United States, 2005–2013. Morb Mortal Wkly Rep. 2014;63(47):1108–12.Google Scholar
  3. 3.
    Hasin DS, Saha TD, Kerridge BT, et al. Prevalence of marijuana use disorders in the United States between 2001–2002 and 2012–2013. JAMA Psychiatry. 2015;72(12):1235–42.PubMedCrossRefGoogle Scholar
  4. 4.
    United Nations Office on Drugs and Crime. World drug report 2012. Vienna: United Nations Office on Drugs and Crime; 2012. Accessed 7 Dec 2015.
  5. 5.
    Hermann PC, Sancho P, Canamero M, et al. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. Gastroenterology. 2014;147(5):1119–33 e4.PubMedCrossRefGoogle Scholar
  6. 6.
    Al-Wadei MH, Al-Wadei HA, Schuller HM. Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors alpha3, alpha5, and alpha7. Mol Cancer Res. 2012;10(2):239–49.PubMedCrossRefGoogle Scholar
  7. 7.
    Lien YC, Wang W, Kuo LJ, et al. Nicotine promotes cell migration through alpha7 nicotinic acetylcholine receptor in gastric cancer cells. Ann Surg Oncol. 2011;18(9):2671–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Sesardic D, Boobis AR, Edwards RJ, et al. A form of cytochrome P450 in man, orthologous to form D in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking. Br J Clin Pharmacol. 1988;26(4):363–72.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Buchthal J, Grund KE, Buchmann A, et al. Induction of cytochrome P4501A by smoking or omeprazole in comparison with UDP-glucuronosyltransferase in biopsies of human duodenal mucosa. Eur J Clin Pharmacol. 1995;47(5):431–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Smith GB, Harper PA, Wong JM, et al. Human lung microsomal cytochrome P4501A1 (CYP1A1) activities: impact of smoking status and CYP1A1, aryl hydrocarbon receptor, and glutathione S-transferase M1 genetic polymorphisms. Cancer Epidemiol Biomark Prev. 2001;10(8):839–53.Google Scholar
  11. 11.
    Benowitz NL, Peng M, Jacob P 3rd. Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism. Clin Pharmacol Ther. 2003;74(5):468–74.PubMedCrossRefGoogle Scholar
  12. 12.
    Jimenez-Garza O, Baccarelli AA, Byun HM, et al. CYP2E1 epigenetic regulation in chronic, low-level toluene exposure: relationship with oxidative stress and smoking habit. Toxicol Appl Pharmacol. 2015;286(3):207–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Czekaj P, Wiaderkiewicz A, Florek E, et al. Tobacco smoke-dependent changes in cytochrome P450 1A1, 1A2, and 2E1 protein expressions in fetuses, newborns, pregnant rats, and human placenta. Arch Toxicol. 2005;79(1):13–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Denton TT, Zhang X, Cashman JR. Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6. Biochem Pharmacol. 2004;67(4):751–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Hukkanen J, Jacob Iii P, Peng M, et al. Effects of nicotine on cytochrome P450 2A6 and 2E1 activities. Br J Clin Pharmacol. 2010;69(2):152–9.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Elsherbiny ME, Brocks DR. The ability of polycyclic aromatic hydrocarbons to alter physiological factors underlying drug disposition. Drug Metab Rev. 2011;43(4):457–75.PubMedCrossRefGoogle Scholar
  17. 17.
    Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol. 2003;43:149–73.PubMedCrossRefGoogle Scholar
  18. 18.
    Monostory K, Pascussi JM, Kobori L, et al. Hormonal regulation of CYP1A expression. Drug Metab Rev. 2009;41(4):547–72.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhou SF, Chan E, Zhou ZW, et al. Insights into the structure, function, and regulation of human cytochrome P450 1A2. Curr Drug Metab. 2009;10(7):713–29.PubMedCrossRefGoogle Scholar
  20. 20.
    Dolwick KM, Schmidt JV, Carver LA, et al. Cloning and expression of a human Ah receptor cDNA. Mol Pharmacol. 1993;44(5):911–7.PubMedGoogle Scholar
  21. 21.
    Zhou SF, Wang B, Yang LP, et al. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev. 2010;42(2):268–354.PubMedCrossRefGoogle Scholar
  22. 22.
    Schmeltz I, Hoffmann D. Nitrogen containing compounds in tobacco and tobacco smoke. Chem Rev. 1977;77(3):295–311.CrossRefGoogle Scholar
  23. 23.
    Saitoh F, Noma M, Kawashima N. The alkaloid contents of sixty Nicotiana species. Phytochemistry. 1985;24(3):477–80.CrossRefGoogle Scholar
  24. 24.
    Pankow JF, Tavakoli AD, Luo W, et al. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chem Res Toxicol. 2003;16(8):1014–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Hukkanen J, Jacob P 3rd, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 2005;57(1):79–115.PubMedCrossRefGoogle Scholar
  26. 26.
    Benowitz NL. Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther. 2008;83(4):531–41.PubMedCrossRefGoogle Scholar
  27. 27.
    Kuehl GE, Murphy SE. N-Glucuronidation of nicotine and cotinine by human liver microsomes and heterologously expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2003;31(11):1361–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu X, Iba MM, Weisel CP. Simultaneous and sensitive measurement of anabasine, nicotine, and nicotine metabolites in human urine by liquid chromatography–tandem mass spectrometry. Clin Chem. 2004;50(12):2323–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Chen G, Giambrone NE, Lazarus P. Glucuronidation of trans-3′-hydroxycotinine by UGT2B17 and UGT2B10. Pharmacogenet Genomics. 2012;22(3):183–90.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Xue Y, Sun D, Daly A, et al. Adaptive evolution of UGT2B17 copy-number variation. Am J Hum Genet. 2008;83(3):337–46.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Zhu AZ, Zhou Q, Cox LS, et al. Variation in trans-3′-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake. PLoS One. 2013;8(8):e70938.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Di YM, Chow VD, Yang LP, et al. Structure, function, regulation and polymorphism of human cytochrome P450 2A6. Curr Drug Metab. 2009;10(7):754–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Kwara A, Lartey M, Sagoe KW, et al. CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients. AIDS. 2009;23(16):2101–6.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Siu EC, Tyndale RF. Selegiline is a mechanism-based inactivator of CYP2A6 inhibiting nicotine metabolism in humans and mice. J Pharmacol Exp Ther. 2008;324(3):992–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Weinberger AH, Reutenauer EL, Jatlow PI, et al. A double-blind, placebo-controlled, randomized clinical trial of oral selegiline hydrochloride for smoking cessation in nicotine-dependent cigarette smokers. Drug Alcohol Depend. 2010;107(2–3):188–95.PubMedCrossRefGoogle Scholar
  36. 36.
    Kahn R, Gorgon L, Jones K, et al. Selegiline transdermal system (STS) as an aid for smoking cessation. Nicotine Tob Res. 2012;14(3):377–82.PubMedCrossRefGoogle Scholar
  37. 37.
    Zevin S, Benowitz NL. Drug interactions with tobacco smoking: an update. Clin Pharmacokinet. 1999;36(6):425–38.PubMedCrossRefGoogle Scholar
  38. 38.
    Facciola G, Hidestrand M, von Bahr C, et al. Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. Eur J Clin Pharmacol. 2001;56(12):881–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Hartter S, Nordmark A, Rose DM, et al. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br J Clin Pharmacol. 2003;56(6):679–82.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ursing C, von Bahr C, Brismar K, et al. Influence of cigarette smoking on melatonin levels in man. Eur J Clin Pharmacol. 2005;61(3):197–201.PubMedCrossRefGoogle Scholar
  41. 41.
    Stormer E, von Moltke LL, Shader RI, et al. Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4. Drug Metab Dispos. 2000;28(10):1168–75.PubMedGoogle Scholar
  42. 42.
    Lind AB, Reis M, Bengtsson F, et al. Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour. Clin Pharmacokinet. 2009;48(1):63–70.PubMedCrossRefGoogle Scholar
  43. 43.
    Jaquenoud Sirot E, Harenberg S, Vandel P, et al. Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression. J Clin Psychopharmacol. 2012;32(5):622–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Hayashi Y, Watanabe T, Aoki A, et al. Factors affecting steady-state plasma concentrations of enantiomeric mirtazapine and its desmethylated metabolites in Japanese psychiatric patients. Pharmacopsychiatry. 2015;48(7):279–85.PubMedCrossRefGoogle Scholar
  45. 45.
    Backman JT, Schroder MT, Neuvonen PJ. Effects of gender and moderate smoking on the pharmacokinetics and effects of the CYP1A2 substrate tizanidine. Eur J Clin Pharmacol. 2008;64(1):17–24.PubMedCrossRefGoogle Scholar
  46. 46.
    Granfors MT, Backman JT, Laitila J, et al. Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol. 2004;57(3):349–53.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Obach RS, Ryder TF. Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010;38(8):1381–91.PubMedCrossRefGoogle Scholar
  48. 48.
    Lecht S, Haroutiunian S, Hoffman A, et al. Rasagiline—a novel MAO B inhibitor in Parkinson’s disease therapy. Ther Clin Risk Manag. 2007;3(3):467–74.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Gurbel PA, Nolin TD, Tantry US. Clopidogrel efficacy and cigarette smoking status. JAMA. 2012;307(23):2495–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Yousef AM, Arafat T, Bulatova NR, et al. Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel. J Clin Pharm Ther. 2008;33(4):439–49.PubMedCrossRefGoogle Scholar
  52. 52.
    Gurbel PA, Bliden KP, Logan DK, et al. The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study. J Am Coll Cardiol. 2013;62(6):505–12.PubMedCrossRefGoogle Scholar
  53. 53.
    Hukkanen J, Jacob P 3rd, Peng M, et al. Effect of nicotine on cytochrome P450 1A2 activity. Br J Clin Pharmacol. 2011;72(5):836–8.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kyaw WT, Nagai M, Kaneta M, et al. Effect of nicotine on the pharmacokinetics of levodopa. Clin Neuropharmacol. 2013;36(2):46–51.PubMedCrossRefGoogle Scholar
  55. 55.
    Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178–84.PubMedCrossRefGoogle Scholar
  56. 56.
    Bondolfi G, Morel F, Crettol S, et al. Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. Ther Drug Monit. 2005;27(4):539–43.PubMedCrossRefGoogle Scholar
  57. 57.
    Zullino DF, Delessert D, Eap CB, et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol. 2002;17(3):141–3.PubMedCrossRefGoogle Scholar
  58. 58.
    Juergens TM. Adverse effects of ropinirole-treated restless leg syndrome (RLS) during smoking cessation. J Clin Sleep Med. 2008;4(4):371–2.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Elkader AK, Brands B, Selby P, et al. Methadone-nicotine interactions in methadone maintenance treatment patients. J Clin Psychopharmacol. 2009;29(3):231–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Asimus S, Hai TN, Van Huong N, et al. Artemisinin and CYP2A6 activity in healthy subjects. Eur J Clin Pharmacol. 2008;64(3):283–92.PubMedCrossRefGoogle Scholar
  61. 61.
    Higashi E, Fukami T, Itoh M, et al. Human CYP2A6 is induced by estrogen via estrogen receptor. Drug Metab Dispos. 2007;35(10):1935–41.PubMedCrossRefGoogle Scholar
  62. 62.
    Benowitz NL, Lessov-Schlaggar CN, Swan GE, et al. Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther. 2006;79(5):480–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Berlin I, Gasior MJ, Moolchan ET. Sex-based and hormonal contraception effects on the metabolism of nicotine among adolescent tobacco-dependent smokers. Nicotine Tob Res. 2007;9(4):493–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Sinues B, Fanlo A, Mayayo E, et al. CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives. Hum Exp Toxicol. 2008;27(5):367–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 2005;78(5):539–48.PubMedCrossRefGoogle Scholar
  66. 66.
    Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Laprairie RB, Bagher AM, Kelly ME, et al. Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor. Br J Pharmacol. 2015;172(20):4790–805.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Thomas A, Baillie GL, Phillips AM, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613–23.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem. 2015;23(7):1377–85.PubMedCrossRefGoogle Scholar
  70. 70.
    Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci. 2006;103(20):7895–900.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Ohlsson A, Lindgren JE, Wahlen A, et al. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980;28(3):409–16.PubMedCrossRefGoogle Scholar
  72. 72.
    Bland TM, Haining RL, Tracy TS, et al. CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin. Biochem Pharmacol. 2005;70(7):1096–103.PubMedCrossRefGoogle Scholar
  73. 73.
    Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80(15):1415–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Hollister LE, Gillespie HK. Action of delta-9-tetrahydrocannabinol: an approach to the active metabolite hypothesis. Clin Pharmacol Ther. 1975;18(06):714–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Sachse-Seeboth C, Pfeil J, Sehrt D, et al. Interindividual variation in the pharmacokinetics of Delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin Pharmacol Ther. 2009;85(3):273–6.PubMedCrossRefGoogle Scholar
  76. 76.
    de Vries M, van Rijckevorsel DGM, Wilder-Smith OHG, von Goor H. Dronabinol and chronic pain: importance of mechanistic considerations. Expert Opin Pharmacother. 2014;15(11):1525-34.PubMedCrossRefGoogle Scholar
  77. 77.
    Jiang R, Yamaori S, Takeda S, et al. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5–6):165–70.PubMedCrossRefGoogle Scholar
  78. 78.
    Hawksworth G, McArdle K. Metabolism and pharmacokinetics of cannabinoids. London: Pharmaceutical Press; 2004.Google Scholar
  79. 79.
    Consroe P, Kennedy K, Schram K. Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacol Biochem Behav. 1991;40(3):517–22.PubMedCrossRefGoogle Scholar
  80. 80.
    Agurell S, Carlsson S, Lindgren JE, et al. Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man: assay of cannabinol and cannabidiol by mass fragmentography. Experientia. 1981;37(10):1090–2.PubMedCrossRefGoogle Scholar
  81. 81.
    Stott CG, White L, Wright S, et al. A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray. Eur J Clin Pharmacol. 2013;69(5):1135–47.PubMedCrossRefGoogle Scholar
  82. 82.
    Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86–95.PubMedCrossRefGoogle Scholar
  83. 83.
    Roth MD, Marques-Magallanes JA, Yuan M, et al. Induction and regulation of the carcinogen-metabolizing enzyme CYP1A1 by marijuana smoke and delta (9)-tetrahydrocannabinol. Am J Respir Cell Mol Biol. 2001;24(3):339–44.PubMedCrossRefGoogle Scholar
  84. 84.
    Yamaori S, Kinugasa Y, Jiang R, et al. Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells. Life Sci. 2015;136:87–93.PubMedCrossRefGoogle Scholar
  85. 85.
    Jiang R, Yamaori S, Okamoto Y, et al. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28(4):332–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Yamaori S, Koeda K, Kushihara M, et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. 2012;27(3):294–300.PubMedCrossRefGoogle Scholar
  87. 87.
    Tjia JF, Colbert J, Back DJ. Theophylline metabolism in human liver microsomes: inhibition studies. J Pharmacol Exp Ther. 1996;276(3):912–7.PubMedGoogle Scholar
  88. 88.
    Wojcikowski J, Boksa J, Daniel WA. Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver—a comparison with other phenothiazines. Biochem Pharmacol. 2010;80(8):1252–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Jusko WJ, Schentag JJ, Clark JH, et al. Enhanced biotransformation of theophylline in marihuana and tobacco smokers. Clin Pharmacol Ther. 1978;24(4):405–10.PubMedCrossRefGoogle Scholar
  90. 90.
    Jusko WJ, Gardner MJ, Mangione A, et al. Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci. 1979;68(11):1358–66.PubMedCrossRefGoogle Scholar
  91. 91.
    Gardner MJ, Tornatore KM, Jusko WJ, et al. Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol. 1983;16(3):271–80.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Chetty M, Miller R, Moodley SV. Smoking and body weight influence the clearance of chlorpromazine. Eur J Clin Pharmacol. 1994;46(6):523–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Engel G, Hofmann U, Heidemann H, et al. Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther. 1996;59:613–23.PubMedCrossRefGoogle Scholar
  94. 94.
    Vesell ES, Passananti GT. Inhibition of drug metabolism in man. Drug Metab Dispos. 1973;1(1):402–10.PubMedGoogle Scholar
  95. 95.
    Benowitz NL, Jones RT. Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism: antipyrine, pentobarbital, and ethanol. Clin Pharmacol Ther. 1977;22(3):259–68.PubMedCrossRefGoogle Scholar
  96. 96.
    Mwenifumbo JC, Sellers EM, Tyndale RF. Nicotine metabolism and CYP2A6 activity in a population of black African descent: impact of gender and light smoking. Drug Alcohol Depend. 2007;89(1):24–33.PubMedCrossRefGoogle Scholar
  97. 97.
    Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet. 1999;36(4):289–304.PubMedCrossRefGoogle Scholar
  98. 98.
    Regazzi M, Maserati R, Villani P, et al. Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV–hepatitis C virus–coinfected subjects. Antimicrob Agents Chemother. 2005;49(2):643–9.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kosel BW, Aweeka FT, Benowitz NL, et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS. 2002;16(4):543–50.PubMedCrossRefGoogle Scholar
  100. 100.
    Giraud C, Tran A, Rey E, et al. In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos. 2004;32(11):1279–86.PubMedGoogle Scholar
  101. 101.
    Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–51.PubMedCrossRefGoogle Scholar
  102. 102.
    Nadulski T, Pragst F, Weinberg G, et al. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit. 2005;27(6):799–810.PubMedCrossRefGoogle Scholar
  103. 103.
    Stott C, White L, Wright S, et al. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus. 2013;2(1):236.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Findlay JW, Van Wyck Fleet J, Smith PG, et al. Pharmacokinetics of bupropion, a novel antidepressant agent, following oral administration to healthy subjects. Eur J Clin Pharmacol. 1981;21(2):127–35.PubMedCrossRefGoogle Scholar
  105. 105.
    Kirchheiner J, Klein C, Meineke I, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003;13(10):619–26.PubMedCrossRefGoogle Scholar
  106. 106.
    Kharasch ED, Mitchell D, Coles R. Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activity. J Clin Pharmacol. 2008;48(4):464–74.PubMedCrossRefGoogle Scholar
  107. 107.
    Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther. 2005;27(11):1685–95.PubMedCrossRefGoogle Scholar
  108. 108.
    Hemauer SJ, Patrikeeva SL, Wang X, et al. Role of transporter-mediated efflux in the placental biodisposition of bupropion and its metabolite, OH-bupropion. Biochem Pharmacol. 2010;80(7):1080–6.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Reese MJ, Wurm RM, Muir KT, et al. An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos. 2008;36(7):1198–201.PubMedCrossRefGoogle Scholar
  110. 110.
    Shad MU, Preskorn SH. A possible bupropion and imipramine interaction. J Clin Psychopharmacol. 1997;17(2):118–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Kennedy SH, McCann SM, Masellis M, et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry. 2002;63(3):181–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Guzey C, Norstrom A, Spigset O. Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion. Ther Drug Monit. 2002;24(3):436–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Kotlyar M, Brauer LH, Tracy TS, et al. Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol. 2005;25(3):226–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Ketter TA, Jenkins JB, Schroeder DH, et al. Carbamazepine but not valproate induces bupropion metabolism. J Clin Psychopharmacol. 1995;15(5):327–33.PubMedCrossRefGoogle Scholar
  115. 115.
    Loboz KK, Gross AS, Williams KM, et al. Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity. Clin Pharmacol Ther. 2006;80(1):75–84.PubMedCrossRefGoogle Scholar
  116. 116.
    Chung JY, Cho JY, Lim HS, et al. Effects of pregnane X receptor (NR1I2) and CYP2B6 genetic polymorphisms on the induction of bupropion hydroxylation by rifampin. Drug Metab Dispos. 2011;39(1):92–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Robertson SM, Penzak SR, Pau A. Drug interactions in the management of HIV infection: an update. Expert Opin Pharmacother. 2007;8(17):2947–63.PubMedCrossRefGoogle Scholar
  118. 118.
    Kharasch ED, Mitchell D, Coles R, et al. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother. 2008;52(5):1663–9.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Hesse LM, Greenblatt DJ, von Moltke LL, et al. Ritonavir has minimal impact on the pharmacokinetic disposition of a single dose of bupropion administered to human volunteers. J Clin Pharmacol. 2006;46(5):567–76.PubMedCrossRefGoogle Scholar
  120. 120.
    Hogeland GW, Swindells S, McNabb JC, et al. Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther. 2007;81(1):69–75.PubMedCrossRefGoogle Scholar
  121. 121.
    Robertson SM, Maldarelli F, Natarajan V, et al. Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects. J Acquir Immune Defic Syndr. 2008;49(5):513–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Turpeinen M, Tolonen A, Uusitalo J, et al. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther. 2005;77(6):553–9.PubMedCrossRefGoogle Scholar
  123. 123.
    Palovaara S, Pelkonen O, Uusitalo J, et al. Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation. Clin Pharmacol Ther. 2003;74(4):326–33.PubMedCrossRefGoogle Scholar
  124. 124.
    Lei HP, Yu XY, Xie HT, et al. Effect of St. John’s wort supplementation on the pharmacokinetics of bupropion in healthy male Chinese volunteers. Xenobiotica. 2010;40(4):275–81.PubMedCrossRefGoogle Scholar
  125. 125.
    Fan L, Wang JC, Jiang F, et al. Induction of cytochrome P450 2B6 activity by the herbal medicine baicalin as measured by bupropion hydroxylation. Eur J Clin Pharmacol. 2009;65(4):403–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Kim H, Kim KB, Ku HY, et al. Identification and characterization of potent CYP2B6 inhibitors in Woohwangcheongsimwon suspension, an herbal preparation used in the treatment and prevention of apoplexy in Korea and China. Drug Metab Dispos. 2008;36(6):1010–5.PubMedCrossRefGoogle Scholar
  127. 127.
    Umegaki K, Saito K, Kubota Y, et al. Ginkgo biloba extract markedly induces pentoxyresorufin O-dealkylase activity in rats. Jpn J Pharmacol. 2002;90(4):345–51.PubMedCrossRefGoogle Scholar
  128. 128.
    Lei HP, Ji W, Lin J, et al. Effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. Br J Clin Pharmacol. 2009;68(2):201–6.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Kim H, Bae SK, Park SJ, et al. Effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, in healthy subjects. Br J Clin Pharmacol. 2010;70(1):126–31.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Faessel HM, Obach RS, Rollema H, et al. A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. Clin Pharmacokinet. 2010;49(12):799–816.PubMedCrossRefGoogle Scholar
  131. 131.
    Feng B, Obach RS, Burstein AH, et al. Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro–in vivo study. Clin Pharmacol Ther. 2008;83(4):567–76.PubMedCrossRefGoogle Scholar
  132. 132.
    Burstein AH, Clark DJ, O’Gorman M, et al. Lack of pharmacokinetic and pharmacodynamic interactions between a smoking cessation therapy, varenicline, and warfarin: an in vivo and in vitro study. J Clin Pharmacol. 2007;47(11):1421–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Faessel HM, Burstein AH, Troutman MD, et al. Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers. Eur J Clin Pharmacol. 2008;64(11):1101–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Urakami Y, Okuda M, Masuda S, et al. Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther. 1998;287(2):800–5.PubMedGoogle Scholar
  135. 135.
    Etter JF, Lukas RJ, Benowitz NL, et al. Cytisine for smoking cessation: a research agenda. Drug Alcohol Depend. 2008;92(1–3):3–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Radchenko EV, Dravolina OA, Bespalov AY. Agonist and antagonist effects of cytisine in vivo. Neuropharmacology. 2015;95:206–14.PubMedCrossRefGoogle Scholar
  137. 137.
    Jeong SH, Newcombe D, Sheridan J, et al. Pharmacokinetics of cytisine, an alpha4 beta2 nicotinic receptor partial agonist, in healthy smokers following a single dose. Drug Test Anal. 2015;7(6):475–82.PubMedCrossRefGoogle Scholar
  138. 138.
    Rollema H, Shrikhande A, Ward KM, et al. Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence. Br J Pharmacol. 2010;160(2):334–45.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Cahill K, Stevens S, Perera R, et al. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013;5:CD009329.PubMedGoogle Scholar
  140. 140.
    Aubin HJ, Luquiens A, Berlin I. Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice. Br J Clin Pharmacol. 2014;77(2):324–36.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Olesen OV, Linnet K. Hydroxylation and demethylation of the tricyclic antidepressant nortriptyline by cDNA-expressed human cytochrome P-450 isozymes. Drug Metab Dispos. 1997;25(6):740–4.PubMedGoogle Scholar
  142. 142.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. J Clin Pharmacol. 1999;39(6):567–77.PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Pharmacy, Box 357630University of WashingtonSeattleUSA

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