Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives

Summary

The effect of chronic (>3 months) administration of low-dose oestrogen-containing (<50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 µg/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Abernethy DR, Divoll M, Ochs HR, Ameer B, Greenblatt DJ (1982) Increased metabolic clearance of acetaminophen with oral contraceptive use. Obstet Gynecol 60: 338–341

    Google Scholar 

  2. 2.

    Abernethy DR, Greenblatt, DJ (1981) Impairment of antipyrine metabolism by low-dose oral contraceptive steroid use. Clin Pharmacol Ther 29: 106–110

    Google Scholar 

  3. 3.

    Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, Shader RI (1982) Impairment of diazepam metabolism by low-dose estrogen oral contraceptive steroids. N Engl J Med 306: 791–792

    Google Scholar 

  4. 4.

    Abernethy DR, Greenblatt DJ, Divoll M, Harmatz JS, Shader RI (1981) Alterations in drug distribution and clearance due to obesity. J Pharmacol Exp Ther 217: 681–685

    Google Scholar 

  5. 5.

    Abernethy DR, Greenblatt DJ, Ochs HR, Weyers D, Divoll M, Harmatz JS, Shader RI (1983) Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Clin Pharmacol Ther 33: 628–632

    Google Scholar 

  6. 6.

    Abernethy DR, Greenblatt DJ, Shader RI (1984) Imipramine disposition in oral contraceptive steroid users. Clin Pharmacol Ther 35: 792–792

    Google Scholar 

  7. 7.

    Aldridge A, Parsons WD, Neims AH (1977) Stimulation of caffeine metabolism in the rat by 3-methylcholanthrene. Life Sci 21: 967–974

    Google Scholar 

  8. 8.

    Alvares AP, Bickers DR, Kappas A (1973) Polychlorinated biphenyls: a new type of inducer of cytochrome P-448 in the liver. Proc Natl Acad Sci (USA) 70: 1321–1325

    Google Scholar 

  9. 9.

    Blanchard J (1982) Protein binding of caffeine in young and elderly males. J Pharm Sci 71: 1415–1418

    Google Scholar 

  10. 10.

    Blanchard J, Mohammadi JD, Conrad KA (1980) Improved liquid-chromatographic determination of caffeine in plasma. Clin Chem 26: 1351–1354

    Google Scholar 

  11. 11.

    Blanchard J, Sawers SJA (1983) The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol 24: 93–98

    Google Scholar 

  12. 12.

    Boekenoogen SJ, Szefler SJ, Jusko WJ (1983) Prednisolone disposition and protein binding in oral contraceptive steroid users. J Clin Endocrinol Metab 56: 702–709

    Google Scholar 

  13. 13.

    Gardner MJ, Tornatore KM, Jusko WJ, Kanarkowski R (1983) Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol 16: 271–280

    Google Scholar 

  14. 14.

    Gibaldi M, Perrier D (1975) Pharmacokinetics. Marcel Dekker New York

    Google Scholar 

  15. 15.

    Goble FC (1975) Sex as a factor in metabolism, toxicity, and efficacy of pharmacodynamic and chemotherapeutic agents. Adv Pharmacol Chemother 13: 173–252

    Google Scholar 

  16. 16.

    Grant DM, Tang BK, Kalow W (1983) Variability in caffeine metabolism. Clin Pharmacol Ther 33: 591–602

    Google Scholar 

  17. 17.

    Greenblatt DJ, Divoll M, Abernethy DR, Harmatz JS, Shader RI (1982) Antipyrine kinetics in the elderly: prediction of age-related changes in benzodiazepine oxidizing capacity. J Pharmacol Exp Ther 220: 120–126

    Google Scholar 

  18. 18.

    Greenblatt DJ, Koch-Weser J (1975) Clinical pharmacokinetics. N Engl J Med 293: 702–705, 964–970

    Google Scholar 

  19. 19.

    Jochemsen R, Van der Graff M, Boeijinga JK, Breimer DD (1982) Influence of sex, menstrual cycle, and oral contraception on the disposition of nitrazepam. Br J Clin Pharmacol 13: 319–324

    Google Scholar 

  20. 20.

    Juchau MR, Fouts JR (1966) Effects of norethynidrel and progesterone on hepatic microsomal drug metabolizing enzyme systems. Biochem Pharmacol 15: 891–898

    Google Scholar 

  21. 21.

    Kappas A, Anderson RE, Conney AH, Alvares AP (1976) Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clin Pharmacol Ther 20: 643–653

    Google Scholar 

  22. 22.

    Mackinnon M, Sutherland E, Simon FE (1977) Effects of ethinyl estradiol on hepatic microsomal proteins and the turnover of cytochrome P-450. J Lab Clin Med 90: 1096–1106

    Google Scholar 

  23. 23.

    Mitchell M, Hanew T, Meredith CG, Schenker S (1983) Effects of oral contraceptive steroids on acetaminophen metabolism and elimination. Clin Pharmacol Ther 34: 48–53

    Google Scholar 

  24. 24.

    Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID (1981) Plasma and salivary pharmacokinetics of caffeine in man. Eur J Clin Pharmacol 21: 45–52

    Google Scholar 

  25. 25.

    Orme MLE (1982) The clinical pharmacology of oral contraceptive steroids. Br J Clin Pharmacol 14: 31–42

    Google Scholar 

  26. 26.

    Parsons WD, Neims AH (1978) Effect of smoking on caffeine clearance. Clin Pharmacol Ther 24: 40–45

    Google Scholar 

  27. 27.

    Patwardhan RV, Desmond PV, Johnson RF, Schenker S (1980) Impaired elimination of caffeine by oral contraceptive steroids. J Lab Clin Med 95: 603–608

    Google Scholar 

  28. 28.

    Patwardhan RV, Mitchell MC, Johnson RF, Schenker S (1983) Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines. Hepatology 3: 248–253

    Google Scholar 

  29. 29.

    Roberts RK, Desmond PV, Wilkinson GR, Schenker S (1979) Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives. Clin Pharmacol Ther 25: 826–831

    Google Scholar 

  30. 30.

    Roberts RK, Grice J, McGuffie C, Heilbronn L (1983) Oral contraceptive steroids impair the elimination of theophylline. J Lab Clin Med 101: 821–825

    Google Scholar 

  31. 31.

    Spector R, Choudhury AK, Chiang CK, Goldberg MJ, Ghoneim MM (1980) Diphenhydramine in orientals and caucasians. Clin Pharmacol Ther 28: 229–234

    Google Scholar 

  32. 32.

    Tephly TR, Mannering GJ (1968) Inhibition of drug metabolism: V. Inhibition of drug metabolism by steroids. Mol Pharmacol 4: 10–14

    Google Scholar 

  33. 33.

    Teunissen MWE, Srivastava AK, Breimer DD (1982) Influence of sex and oral contraceptives on antipyrine metabolite formation. Clin Pharmacol Ther 32: 240–246

    Google Scholar 

  34. 34.

    Tornatore KM, Kanarkowski R, McCarthy TL, Gardner MJ, Yurchak AM, Jusko WJ (1982) Effect of chronic oral contraceptive steroids on theophylline disposition. Eur J Clin Pharmacol 23: 129–134

    Google Scholar 

  35. 35.

    Wagner JG (1975) Fundamentals of clinical pharmacokinetics. Drug Intell (Hamilton, IL)

    Google Scholar 

  36. 36.

    Wietholtz H, Voegelin M, Arnaud MJ, Bircher J, Preisig R (1981) Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test. Eur J Clin Pharmacol 21: 53–59

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Abernethy, D.R., Todd, E.L. Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives. Eur J Clin Pharmacol 28, 425–428 (1985). https://doi.org/10.1007/BF00544361

Download citation

Key words

  • caffeine
  • oral contraceptives
  • pharmacokinetics
  • elimination half-life