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. 1987 Nov;80(5):1466–1471. doi: 10.1172/JCI113227

Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics.

H C Porchet 1, N L Benowitz 1, L B Sheiner 1, J R Copeland 1
PMCID: PMC442405  PMID: 3680508

Abstract

Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for a given nicotine concentration during the rising phase of nicotine concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict "brain" concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ABELE G., CASPERS H. Hirnelektrische Untersuchungen zur Frage der quantitativen Beziehungen zwischen Blutalkoholgehalt und Alkoholeffekt. Dtsch Z Gesamte Gerichtl Med. 1956;45(6):492–509. [PubMed] [Google Scholar]
  2. ASCHAN G., BERGSTEDT M., GOLDBERG L., LAURELL L. Positional nystagmus in man during and after alcohol intoxication. Q J Stud Alcohol. 1956 Sep;17(3):381–405. [PubMed] [Google Scholar]
  3. Armstrong P. W., Moffat J. A. Tolerance to organic nitrates: clinical and experimental perspectives. Am J Med. 1983 Jun 27;74(6B):73–84. doi: 10.1016/0002-9343(83)90857-4. [DOI] [PubMed] [Google Scholar]
  4. Benowitz N. L. Clinical pharmacology of nicotine. Annu Rev Med. 1986;37:21–32. doi: 10.1146/annurev.me.37.020186.000321. [DOI] [PubMed] [Google Scholar]
  5. Benowitz N. L., Jacob P., 3rd, Jones R. T., Rosenberg J. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther. 1982 May;221(2):368–372. [PubMed] [Google Scholar]
  6. COMROE J. H., Jr The pharmacological actions of nicotine. Ann N Y Acad Sci. 1960 Sep 27;90:48–51. doi: 10.1111/j.1749-6632.1960.tb32616.x. [DOI] [PubMed] [Google Scholar]
  7. Chow M. J., Ambre J. J., Ruo T. I., Atkinson A. J., Jr, Bowsher D. J., Fischman M. W. Kinetics of cocaine distribution, elimination, and chronotropic effects. Clin Pharmacol Ther. 1985 Sep;38(3):318–324. doi: 10.1038/clpt.1985.179. [DOI] [PubMed] [Google Scholar]
  8. Galeazzi R. L., Benet L. Z., Sheiner L. B. Relationship between the pharmacokinetics and pharmacodynamics of procainamide. Clin Pharmacol Ther. 1976 Sep;20(3):278–289. doi: 10.1002/cpt1976203278. [DOI] [PubMed] [Google Scholar]
  9. Harden T. K. Agonist-induced desensitization of the beta-adrenergic receptor-linked adenylate cyclase. Pharmacol Rev. 1983 Mar;35(1):5–32. [PubMed] [Google Scholar]
  10. Jacob P., 3rd, Wilson M., Benowitz N. L. Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids. J Chromatogr. 1981 Jan 2;222(1):61–70. doi: 10.1016/s0378-4347(00)81033-6. [DOI] [PubMed] [Google Scholar]
  11. Kalant H., LeBlanc A. E., Gibbins R. J. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev. 1971 Sep;23(3):135–191. [PubMed] [Google Scholar]
  12. Katz M., Sokal M. M. Skin perfusion in pregnancy. Am J Obstet Gynecol. 1980 May 1;137(1):30–33. doi: 10.1016/0002-9378(80)90381-6. [DOI] [PubMed] [Google Scholar]
  13. Lee B. L., Benowitz N. L., Jacob P., 3rd Influence of tobacco abstinence on the disposition kinetics and effects of nicotine. Clin Pharmacol Ther. 1987 Apr;41(4):474–479. doi: 10.1038/clpt.1987.59. [DOI] [PubMed] [Google Scholar]
  14. Leier C. V. Nitrate tolerance. Am Heart J. 1985 Jul;110(1 Pt 2):224–232. doi: 10.1016/0002-8703(85)90491-0. [DOI] [PubMed] [Google Scholar]
  15. Marks M. J., Romm E., Gaffney D. K., Collins A. C. Nicotine-induced tolerance and receptor changes in four mouse strains. J Pharmacol Exp Ther. 1986 Jun;237(3):809–819. [PubMed] [Google Scholar]
  16. Murley R. A tale of turbulent times. Br Med J (Clin Res Ed) 1984 Dec 22;289(6460):1782–1783. doi: 10.1136/bmj.289.6460.1782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Neutze J. M., Wyler F., Rudolph A. M. Use of radioactive microspheres to assess distribution of cardiac output in rabbits. Am J Physiol. 1968 Aug;215(2):486–495. doi: 10.1152/ajplegacy.1968.215.2.486. [DOI] [PubMed] [Google Scholar]
  18. Oldendorf W. H. Lipid solubility and drug penetration of the blood brain barrier. Proc Soc Exp Biol Med. 1974 Dec;147(3):813–815. doi: 10.3181/00379727-147-38444. [DOI] [PubMed] [Google Scholar]
  19. Peck C. C., Beal S. L., Sheiner L. B., Nichols A. I. Extended least squares nonlinear regression: a possible solution to the "choice of weights" problem in analysis of individual pharmacokinetic data. J Pharmacokinet Biopharm. 1984 Oct;12(5):545–558. doi: 10.1007/BF01060132. [DOI] [PubMed] [Google Scholar]
  20. Rosenberg J., Benowitz N. L., Jacob P., Wilson K. M. Disposition kinetics and effects of intravenous nicotine. Clin Pharmacol Ther. 1980 Oct;28(4):517–522. doi: 10.1038/clpt.1980.196. [DOI] [PubMed] [Google Scholar]
  21. Russell M. A., Feyerabend C. Cigarette smoking: a dependence on high-nicotine boli. Drug Metab Rev. 1978;8(1):29–57. doi: 10.3109/03602537808993776. [DOI] [PubMed] [Google Scholar]
  22. Sibley D. R., Lefkowitz R. J. Molecular mechanisms of receptor desensitization using the beta-adrenergic receptor-coupled adenylate cyclase system as a model. Nature. 1985 Sep 12;317(6033):124–129. doi: 10.1038/317124a0. [DOI] [PubMed] [Google Scholar]
  23. Stålhandske T. Effects of increased liver metabolism of nicotine on its uptake, elimination and toxicity in mice. Acta Physiol Scand. 1970 Oct;80(2):222–234. doi: 10.1111/j.1748-1716.1970.tb04786.x. [DOI] [PubMed] [Google Scholar]
  24. Su C. Actions of nicotine and smoking on circulation. Pharmacol Ther. 1982;17(1):129–141. doi: 10.1016/0163-7258(82)90050-x. [DOI] [PubMed] [Google Scholar]
  25. Tur E., Guy R. H., Tur M., Maibach H. I. Noninvasive assessment of local nicotinate pharmacodynamics by photoplethysmography. J Invest Dermatol. 1983 Jun;80(6):499–503. doi: 10.1111/1523-1747.ep12535042. [DOI] [PubMed] [Google Scholar]
  26. Wagner J. G. A safe method for rapidly achieving plasma concentration plateaus. Clin Pharmacol Ther. 1974 Oct;16(4):691–700. doi: 10.1002/cpt1974164691. [DOI] [PubMed] [Google Scholar]

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