Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1995 Jan;39(1):65–69. doi: 10.1111/j.1365-2125.1995.tb04411.x

Caffeine as a metabolic probe: a comparison of the metabolic ratios used to assess CYP1A2 activity.

L J Notarianni 1, S E Oliver 1, P Dobrocky 1, P N Bennett 1, B W Silverman 1
PMCID: PMC1364983  PMID: 7756101

Abstract

1. Caffeine is widely used as an in vivo probe for CYP1A2; the distribution/activity of this enzyme is reported to be reflected by metabolic ratios. 2. Several metabolic ratios using different combinations of urinary metabolites have been used to measure CYP1A2, with varying conclusions on its distribution. 3. A mathematical comparison of five metabolic ratios claiming to reflect CYP1A2 activity was made using data from 237 healthy volunteers. 4. All five metabolic ratios were symmetrically distributed. The five ratios however, measured at least three different parameters, with no one ratio correlating exactly with any other. 5. Data in the literature claiming to measure CYP1A2 using caffeine may reflect other parameters. 6. The complex metabolism of caffeine together with different parameters controlling the renal clearance of each metabolite, makes the use of urinary metabolic ratios an inaccurate probe for assessing the distribution of CYP1A2 activity in populations.

Full text

PDF
65

Selected References

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

  1. Butler M. A., Iwasaki M., Guengerich F. P., Kadlubar F. F. Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7696–7700. doi: 10.1073/pnas.86.20.7696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Butler M. A., Lang N. P., Young J. F., Caporaso N. E., Vineis P., Hayes R. B., Teitel C. H., Massengill J. P., Lawsen M. F., Kadlubar F. F. Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics. 1992 Jun;2(3):116–127. doi: 10.1097/00008571-199206000-00003. [DOI] [PubMed] [Google Scholar]
  3. Campbell M. E., Grant D. M., Inaba T., Kalow W. Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metab Dispos. 1987 Mar-Apr;15(2):237–249. [PubMed] [Google Scholar]
  4. Campbell M. E., Spielberg S. P., Kalow W. A urinary metabolite ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther. 1987 Aug;42(2):157–165. doi: 10.1038/clpt.1987.126. [DOI] [PubMed] [Google Scholar]
  5. Dobrocky P., Bennett P. N., Notarianni L. J. Rapid method for the routine determination of caffeine and its metabolites by high-performance liquid chromatography. J Chromatogr. 1994 Jan 14;652(1):104–108. doi: 10.1016/0378-4347(93)e0369-2. [DOI] [PubMed] [Google Scholar]
  6. EVANS D. A., MANLEY K. A., McKUSICK V. A. Genetic control of isoniazid metabolism in man. Br Med J. 1960 Aug 13;2(5197):485–491. doi: 10.1136/bmj.2.5197.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Grant D. M., Tang B. K., Campbell M. E., Kalow W. Effect of allopurinol on caffeine disposition in man. Br J Clin Pharmacol. 1986 Apr;21(4):454–458. doi: 10.1111/j.1365-2125.1986.tb05222.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grant D. M., Tang B. K., Kalow W. Variability in caffeine metabolism. Clin Pharmacol Ther. 1983 May;33(5):591–602. doi: 10.1038/clpt.1983.80. [DOI] [PubMed] [Google Scholar]
  9. Gu L., Gonzalez F. J., Kalow W., Tang B. K. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics. 1992 Apr;2(2):73–77. doi: 10.1097/00008571-199204000-00004. [DOI] [PubMed] [Google Scholar]
  10. Kadlubar F. F., Talaska G., Butler M. A., Teitel C. H., Massengill J. P., Lang N. P. Determination of carcinogenic arylamine N-oxidation phenotype in humans by analysis of caffeine urinary metabolites. Prog Clin Biol Res. 1990;340B:107–114. [PubMed] [Google Scholar]
  11. Kalow W., Tang B. K. The use of caffeine for enzyme assays: a critical appraisal. Clin Pharmacol Ther. 1993 May;53(5):503–514. doi: 10.1038/clpt.1993.63. [DOI] [PubMed] [Google Scholar]
  12. Kalow W., Tang B. K. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther. 1991 Nov;50(5 Pt 1):508–519. doi: 10.1038/clpt.1991.176. [DOI] [PubMed] [Google Scholar]
  13. Lelo A., Miners J. O., Robson R. A., Birkett D. J. Quantitative assessment of caffeine partial clearances in man. Br J Clin Pharmacol. 1986 Aug;22(2):183–186. doi: 10.1111/j.1365-2125.1986.tb05247.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mahgoub A., Idle J. R., Dring L. G., Lancaster R., Smith R. L. Polymorphic hydroxylation of Debrisoquine in man. Lancet. 1977 Sep 17;2(8038):584–586. doi: 10.1016/s0140-6736(77)91430-1. [DOI] [PubMed] [Google Scholar]
  15. Relling M. V., Lin J. S., Ayers G. D., Evans W. E. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther. 1992 Dec;52(6):643–658. doi: 10.1038/clpt.1992.203. [DOI] [PubMed] [Google Scholar]
  16. Rost K. L., Roots I. Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: coincidence with plasma clearance and breath test. Clin Pharmacol Ther. 1994 Apr;55(4):402–411. doi: 10.1038/clpt.1994.49. [DOI] [PubMed] [Google Scholar]
  17. Tang B. K., Zhou Y., Kadar D., Kalow W. Caffeine as a probe for CYP1A2 activity: potential influence of renal factors on urinary phenotypic trait measurements. Pharmacogenetics. 1994 Jun;4(3):117–124. [PubMed] [Google Scholar]
  18. Vistisen K., Poulsen H. E., Loft S. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis. 1992 Sep;13(9):1561–1568. doi: 10.1093/carcin/13.9.1561. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES