Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1990 Apr;34(4):594–599. doi: 10.1128/aac.34.4.594

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes.

M Sarkar 1, R E Polk 1, P S Guzelian 1, C Hunt 1, H T Karnes 1
PMCID: PMC171649  PMID: 2344166

Abstract

Some quinolone antibiotics cause increases in levels of theophylline in plasma that lead to serious adverse effects. We investigated the mechanism of this interaction by developing an in vitro system of human liver microsomes. Theophylline (1,3-dimethylxanthine) was incubated with human liver microsomes in the presence of enoxacin, ciprofloxacin, norfloxacin, or ofloxacin. Theophylline, its demethylated metabolites (3-methylxanthine and 1-methylxanthine), and its hydroxylated metabolite (1,3-dimethyluric acid) were measured by high-pressure liquid chromatography, and Km and Vmax values were estimated. Enoxacin and ciprofloxacin selectively blocked the two N demethylations; they significantly inhibited the hydroxylation only at high concentrations. Norfloxacin and ofloxacin caused little or no inhibition of the three metabolites at comparable concentrations. The extent of inhibition was reproducible in five different human livers. Inhibition enzyme kinetics revealed that enoxacin caused competitive and mixed competitive types of inhibition. The oxo metabolite of enoxacin caused little inhibition of theophylline metabolism and was much less potent than the parent compound. Nonspecific inhibition of cytochrome P-450 was ruled out since erythromycin N demethylation (cytochrome P-450 mediated) was unaffected in the presence of enoxacin. These in vitro data correlate with the clinical interaction described for these quinolones and theophylline. We conclude that some quinolones are potent and selective inhibitors of specific isozymes of human cytochrome P-450 that are responsible for theophylline metabolism. This in vitro system may be useful as a model to screen similar compounds for early identification of potential drug interactions.

Full text

PDF
594

Selected References

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

  1. Beckmann J., Elsässer W., Gundert-Remy U., Hertrampf R. Enoxacin--a potent inhibitor of theophylline metabolism. Eur J Clin Pharmacol. 1987;33(3):227–230. doi: 10.1007/BF00637553. [DOI] [PubMed] [Google Scholar]
  2. Birkett D. J., Miners J. O., Attwood J. Secondary metabolism of theophylline biotransformation products in man--route of formation of 1-methyluric acid. Br J Clin Pharmacol. 1983 Jan;15(1):117–119. doi: 10.1111/j.1365-2125.1983.tb01475.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  4. Lohmann S. M., Miech R. P. Theophylline metabolism by the rat liver microsomal system. J Pharmacol Exp Ther. 1976 Jan;196(1):213–225. [PubMed] [Google Scholar]
  5. Maesen F. P., Teengs J. P., Baur C., Davies B. I. Quinolones and raised plasma concentrations of theophylline. Lancet. 1984 Sep 1;2(8401):530–530. doi: 10.1016/s0140-6736(84)92617-5. [DOI] [PubMed] [Google Scholar]
  6. Mulder G. J., Nagelkerke J. F., Tijdens R. B., Wijnands W. J., Van der Mark E. J. Inhibition of the oxidative metabolism of theophylline in isolated rat hepatocytes by the quinolone antibiotic enoxacin and its metabolite oxoenoxacin, but not by ofloxacin. Biochem Pharmacol. 1988 Jul 1;37(13):2565–2568. doi: 10.1016/0006-2952(88)90247-x. [DOI] [PubMed] [Google Scholar]
  7. NASH T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J. 1953 Oct;55(3):416–421. doi: 10.1042/bj0550416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Neuman M. Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin Pharmacokinet. 1988 Feb;14(2):96–121. doi: 10.2165/00003088-198814020-00003. [DOI] [PubMed] [Google Scholar]
  9. Niki Y., Soejima R., Kawane H., Sumi M., Umeki S. New synthetic quinolone antibacterial agents and serum concentration of theophylline. Chest. 1987 Oct;92(4):663–669. doi: 10.1378/chest.92.4.663. [DOI] [PubMed] [Google Scholar]
  10. Ogilvie R. I. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet. 1978 Jul-Aug;3(4):267–293. doi: 10.2165/00003088-197803040-00002. [DOI] [PubMed] [Google Scholar]
  11. Robson R. A., Matthews A. P., Miners J. O., McManus M. E., Meyer U. A., Hall P. M., Birkett D. J. Characterisation of theophylline metabolism in human liver microsomes. Br J Clin Pharmacol. 1987 Sep;24(3):293–300. doi: 10.1111/j.1365-2125.1987.tb03172.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Robson R. A., Miners J. O., Matthews A. P., Stupans I., Meller D., McManus M. E., Birkett D. J. Characterisation of theophylline metabolism by human liver microsomes. Inhibition and immunochemical studies. Biochem Pharmacol. 1988 May 1;37(9):1651–1659. doi: 10.1016/0006-2952(88)90423-6. [DOI] [PubMed] [Google Scholar]
  13. Rogge M. C., Solomon W. R., Sedman A. J., Welling P. G., Toothaker R. D., Wagner J. G. The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition. Clin Pharmacol Ther. 1988 Nov;44(5):579–587. doi: 10.1038/clpt.1988.197. [DOI] [PubMed] [Google Scholar]
  14. Sano M., Kawakatsu K., Ohkita C., Yamamoto I., Takeyama M., Yamashina H., Goto M. Effects of enoxacin, ofloxacin and norfloxacin on theophylline disposition in humans. Eur J Clin Pharmacol. 1988;35(2):161–165. doi: 10.1007/BF00609246. [DOI] [PubMed] [Google Scholar]
  15. Watkins P. B., Wrighton S. A., Maurel P., Schuetz E. G., Mendez-Picon G., Parker G. A., Guzelian P. S. Identification of an inducible form of cytochrome P-450 in human liver. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6310–6314. doi: 10.1073/pnas.82.18.6310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Wijnands W. J., Vree T. B. Interaction between the fluoroquinolones and the bronchodilator theophylline. J Antimicrob Chemother. 1988 Sep;22 (Suppl 100):109–114. doi: 10.1093/jac/22.supplement_c.109. [DOI] [PubMed] [Google Scholar]
  17. Wijnands W. J., Vree T. B., Van Herwaarden C. L. Enoxacin decreases the clearance of theophylline in man. Br J Clin Pharmacol. 1985 Dec;20(6):583–588. doi: 10.1111/j.1365-2125.1985.tb05115.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wijnands W. J., Vree T. B., van Herwaarden C. L. The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol. 1986 Dec;22(6):677–683. doi: 10.1111/j.1365-2125.1986.tb02957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Wijnands W. J., van Herwaarden C. L., Vree T. B. Enoxacin raises plasma theophylline concentrations. Lancet. 1984 Jul 14;2(8394):108–109. doi: 10.1016/s0140-6736(84)90283-6. [DOI] [PubMed] [Google Scholar]
  20. Wrighton S. A., Thomas P. E., Willis P., Maines S. L., Watkins P. B., Levin W., Guzelian P. S. Purification of a human liver cytochrome P-450 immunochemically related to several cytochromes P-450 purified from untreated rats. J Clin Invest. 1987 Oct;80(4):1017–1022. doi: 10.1172/JCI113154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. van der Hoeven T. A., Coon M. J. Preparation and properties of partially purified cytochrome P-450 and reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase from rabbit liver microsomes. J Biol Chem. 1974 Oct 10;249(19):6302–6310. [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES