Skip to main content
PMC home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1991 Jul;32(1):17–21. doi: 10.1111/j.1365-2125.1991.tb05607.x

The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.

S M Sim 1, D J Back 1, A M Breckenridge 1
PMCID: PMC1368487  PMID: 1909542

Abstract

1. Zidovudine (3'-azido-3'-deoxythymidine; AZT) is the drug of proven efficacy available for the treatment of patients with AIDS or ARC. It is eliminated mainly by hepatic glucuronidation. Therefore, interference with this metabolic pathway may lead to enhancement of AZT effect or to increased toxicity of the drug. We have examined the effect of a number of drugs which themselves undergo glucuronidation on AZT conjugation by human liver microsomes in vitro. 2. AZT glucuronidation followed Michaelis-Menten kinetics. The apparent Km and Vmax values (mean +/- s.d., n = 5), were 2.60 +/- 0.52 mM and 68.0 +/- 23.4 nmol h-1 mg-1, respectively, as determined from Eadie-Hofstee plots. 3. Dideoxyinosine, sulphanilamide and paracetamol were essentially non-inhibitory at concentrations up to 10 mM (4 times the concentration of AZT in the incubation). The most marked inhibitory effects were seen with indomethacin, naproxen, chloramphenicol, probenecid and ethinyloestradiol, with enzyme activity decreased by 97.7, 94.9, 88.7, 83.4% and 79.0%, respectively, at a concentration of 10 mM. Other compounds producing some inhibition of AZT conjugation were oxazepam, salicylic acid and acetylsalicylic acid. 4. Further studies are necessary to characterise the inhibition observed but the method described enables a screen of potentially important drug interactions to be carried out.

Full text

PDF
19

Selected References

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

  1. Cload P. A. A review of the pharmacokinetics of zidovudine in man. J Infect. 1989 Jan;18 (Suppl 1):15–21. doi: 10.1016/s0163-4453(89)80076-3. [DOI] [PubMed] [Google Scholar]
  2. Cretton E. M., Waterhous D. V., Bevan R., Sommadossi J. P. Glucuronidation of 3'-azido-3'-deoxythymidine by rat and human liver microsomes. Drug Metab Dispos. 1990 May-Jun;18(3):369–372. [PubMed] [Google Scholar]
  3. De Simone C., Tzantzoglou S., Vullo V., Catania S., Trinchieri V. Inosine pranobex and zidovudine metabolism. Lancet. 1989 Oct 21;2(8669):977–977. doi: 10.1016/s0140-6736(89)90982-3. [DOI] [PubMed] [Google Scholar]
  4. Good S. S., Koble C. S., Crouch R., Johnson R. L., Rideout J. L., de Miranda P. Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans. Drug Metab Dispos. 1990 May-Jun;18(3):321–326. [PubMed] [Google Scholar]
  5. Good S. S., Reynolds D. J., de Miranda P. Simultaneous quantification of zidovudine and its glucuronide in serum by high-performance liquid chromatography. J Chromatogr. 1988 Sep 23;431(1):123–133. doi: 10.1016/s0378-4347(00)83075-3. [DOI] [PubMed] [Google Scholar]
  6. Hartman N. R., Yarchoan R., Pluda J. M., Thomas R. V., Marczyk K. S., Broder S., Johns D. G. Pharmacokinetics of 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin Pharmacol Ther. 1990 May;47(5):647–654. doi: 10.1038/clpt.1990.86. [DOI] [PubMed] [Google Scholar]
  7. Kornhauser D. M., Petty B. G., Hendrix C. W., Woods A. S., Nerhood L. J., Bartlett J. G., Lietman P. S. Probenecid and zidovudine metabolism. Lancet. 1989 Aug 26;2(8661):473–475. doi: 10.1016/s0140-6736(89)92087-4. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Pacifici G. M., Back D. J. Sulphation and glucuronidation of ethinyloestradiol in human liver in vitro. J Steroid Biochem. 1988 Sep;31(3):345–349. doi: 10.1016/0022-4731(88)90360-3. [DOI] [PubMed] [Google Scholar]
  10. Pullar T., Myall O., Haigh J. R., Lowe J. R., Dixon J. S., Bird H. A. The effect of allopurinol on the steady-state pharmacokinetics of indomethacin. Br J Clin Pharmacol. 1988 Jun;25(6):755–757. doi: 10.1111/j.1365-2125.1988.tb05263.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Purba H. S., Maggs J. L., Orme M. L., Back D. J., Park B. K. The metabolism of 17 alpha-ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites. Br J Clin Pharmacol. 1987 Apr;23(4):447–453. doi: 10.1111/j.1365-2125.1987.tb03074.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Resetar A., Spector T. Glucuronidation of 3'-azido-3'-deoxythymidine: human and rat enzyme specificity. Biochem Pharmacol. 1989 May 1;38(9):1389–1393. doi: 10.1016/0006-2952(89)90177-9. [DOI] [PubMed] [Google Scholar]
  13. Taburet A. M., Naveau S., Zorza G., Colin J. N., Delfraissy J. F., Chaput J. C., Singlas E. Pharmacokinetics of zidovudine in patients with liver cirrhosis. Clin Pharmacol Ther. 1990 Jun;47(6):731–739. doi: 10.1038/clpt.1990.101. [DOI] [PubMed] [Google Scholar]
  14. Tephly T. R., Burchell B. UDP-glucuronosyltransferases: a family of detoxifying enzymes. Trends Pharmacol Sci. 1990 Jul;11(7):276–279. doi: 10.1016/0165-6147(90)90008-v. [DOI] [PubMed] [Google Scholar]
  15. de Miranda P., Good S. S., Yarchoan R., Thomas R. V., Blum M. R., Myers C. E., Broder S. Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex. Clin Pharmacol Ther. 1989 Nov;46(5):494–500. doi: 10.1038/clpt.1989.176. [DOI] [PubMed] [Google Scholar]
  16. van den Ouweland F. A., Franssen M. J., van de Putte L. B., Tan Y., van Ginneken C. A., Gribnau F. W. Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation. Br J Clin Pharmacol. 1987 Feb;23(2):189–193. doi: 10.1111/j.1365-2125.1987.tb03028.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES