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European Journal of Clinical Pharmacology

, Volume 40, Issue 3, pp 273–278 | Cite as

Effects of caffeine with repeated dosing

  • C. P. Denaro
  • C. R. Brown
  • P. JacobIII
  • N. L. Benowitz
Originals

Summary

We have recently demonstrated dose-dependency of caffeine metabolism under multiple dosing conditions. Whether there are persistent pharmacodynamic actions of caffeine under such circumstances is the focus of this report. Nine healthy subjects were given, in randomized 5 day blocks, placebo, 4.2 (low) and 12 (high) mg · kg−1 · day−1 of caffeine in 6 divided doses.

After 5 days, complete tolerance developed to the effects of caffeine on blood pressure, heart rate and plasma glucose concentrations. The 24-h area under the curve (AUC) for plasma norepinephrine and the AUC for the total sum of free fatty acids (FFA) both demonstrated a trend to increase with the high dose caffeine treatment. When the AUC for norepinephrine was split into 12 h time periods, a significant difference between the placebo and the high dose treatment block was seen.

We conclude that regular consumption of 12 mg · kg−1 of caffeine per day (equivalent to approximately 6 to 11 cups of coffee per day) may produce pharmacodynamic effects not completely compensated for by the development of tolerance. Mechanisms of tolerance may be overwhelmed by the nonlinear accumulation of caffeine and other methylxanthines in the body when caffeine metabolism becomes saturable.

Key words

Caffeine tolerance catecholamines free fatty acids dose-dependency 

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References

  1. 1.
    LaCroix AZ, Mead LA, Liang KY, Thomas CB, Pearson TA (1986) Coffee consumption and the incidence of coronary heart disease. N Engl J Med 315: 977–982Google Scholar
  2. 2.
    LeGrady D, Dyer AR, Shekelle RB, Stamler J, Liu K, Paul O, Lepper M, Shyrock AM (1987) Coffee consumption and mortality in the Chicago Western Electric Company study. Am J Epidemiol 126: 803–812Google Scholar
  3. 3.
    Rosenberg L, Werler MM, Kaufman DW, Shapiro S (1987) Coffee drinking and myocardial infarction in young women: an update. Am J Epidemiol 126: 147–149Google Scholar
  4. 4.
    Rosenberg L, Palmer JR, Kelly JP, Kaufman DW, Shapiro S (1988) Coffee drinking and nonfatal myocardial infarction in men under 55 years of age. Am J Epidemiol 128: 570–578Google Scholar
  5. 5.
    Thelle DS, Arnesen E, Forde OH (1983) The Tromso heart study: does coffee raise serum cholesterol? N Engl J Med 308: 1454–1457Google Scholar
  6. 6.
    Bak AAA, Grobbee DE (1989) The effect on serum cholesterol levels of coffee brewed by filtering or boiling. N Engl J Med 321: 1432–1437Google Scholar
  7. 7.
    Williams PT, Wood PD, Vranizan KM, Albers JJ, Garay SC, Taylor CB (1985) Coffee intake and elevated cholesterol and apolipoprotein B levels in men. JAMA 253: 1407–1411Google Scholar
  8. 8.
    Davis BR, Curb JD, Borhani NO, Prineas RJ, Molteni A (1988) Coffee consumption and serum cholesterol in the Hypertension Detection and Follow up Program. Am J Epidemiol 128: 124–136Google Scholar
  9. 9.
    Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield W, Shand DG, Oates JA (1978) Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 298: 181–186Google Scholar
  10. 10.
    Jung RT, Shetty PS, James WPT, Barrand MA, Callingham BA (1981) Caffeine: Its effect on catecholamines and metabolism in lean and obese humans. Clin Sci 60: 527–535Google Scholar
  11. 11.
    Bellet S, Kershbaum A, Finck EM (1968) Response of free fatty acids to coffee and caffeine. Metabolism 17: 702–707Google Scholar
  12. 12.
    Avogaro P, Capri C, Pais M, Cazzolato G (1973) Plasma and urine cortisol behaviour and fat mobilization in man after coffee ingestion. Isr J Med Sci 9: 114–119Google Scholar
  13. 13.
    Dobmeyer DJ, Stine RA, Leier CV, Greenberg R, Schaal SF (1983) The arrhythmogenic effects of caffeine in human beings. N Engl J Med 308: 814–816Google Scholar
  14. 14.
    Sutherland DJ, McPherson DD, Renton KW, Spencer CA, Montague TJ (1985) The effect of caffeine on cardiac rate, rhythm and ventricular repolarization. Chest 87: 319–324Google Scholar
  15. 15.
    Fredholm BB (1985) On the mechanism of action of theophylline and caffeine. Acta Med Scand 217: 149–153Google Scholar
  16. 16.
    Robertson D, Wade D, Workman R, Woosley RL, Oates JA (1981) Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest 67: 1111–1117Google Scholar
  17. 17.
    Robertson D, Hollister AS, Kincaid D, Workman M, Goldberg R, Tung C, Smith B (1984) Caffeine and hypertension. Am J Med 77: 54–60Google Scholar
  18. 18.
    Denaro CP, Brown CR, Wilson M, Jacob P, Benowitz NL (1990) Dose-dependency of caffeine metabolism. Clin Pharmacol Ther 48: 277–285Google Scholar
  19. 19.
    Tang-Liu DD, Williams RL, Riegelman S (1982) Nonlinear theophylline elimination. Clin Pharmacol Ther 31: 358–369Google Scholar
  20. 20.
    Hjemdahl P, Daleskog M, Kahan T (1979) Determination of plasma catecholamines by high performance liquid chromatography with electrochemical detection: comparison with a radioenzymatic method. Life Sci 25: 131–138Google Scholar
  21. 21.
    Higa S, Suzuki T, Hayashi A, Tsuge I, Yamamura Y (1977) Isolation of catecholamines in biological fluids by boric acid gel. Anal Biochem 77: 18–24Google Scholar
  22. 22.
    Belfrage P, Vaughan M (1969) Simple liquid-liquid partition system for isolation of labeled oleic acid from mixtures with glycerides, J Lipid Res 10: 341–345Google Scholar
  23. 23.
    Wu MS, Jeng CY, Hollenbeck CB, Chen YDI, Jaspan J, Reaven GM (1990) Does glucagon increase plasma free fatty acid concentration in humans with normal glucose tolerance? J Clin Endocrinol Metab 70: 410–416Google Scholar
  24. 24.
    Pfeifer RW, Notari RE (1988) Predicting caffeine plasma concentrations resulting from the consumption of food or beverages: a simple method and its origin. Drug Intell Clin Pharm 22: 953–959Google Scholar
  25. 25.
    Onrot J, Goldberg MR, Biaggioni I, Hollister AS, Kincaid D, Robertson D (1985) Hemodynamic and humoral effects of caffeine in autonomic failure. N Engl J Med 313: 549–554Google Scholar
  26. 26.
    Smits P, Thien T, van't Laar A (1985) Circulatory effects of coffee in relation to the pharmacokinetics of caffeine. Am J Cardiol 56: 958–963Google Scholar
  27. 27.
    Yokogoshi H, Mochizuki S, Takahata M, Quazi S, Yoshida A (1983) The hypercholesterolemic effect of caffeine-containing beverages and xanthine derivatives in rats. Nutr Rep Int 28: 805–814Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • C. P. Denaro
    • 1
  • C. R. Brown
    • 1
  • P. JacobIII
    • 1
  • N. L. Benowitz
    • 1
  1. 1.Division of Clinical Pharmacology and Experimental Therapeutics, Department of MedicineUniversity of CaliforniaSan FranciscoUSA

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