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

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 incre...

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Main Authors: Sim, S.M., Back, D.J., Breckenridge, A.M.
Format: Article
Published: Blackwell Publishing 1991
Subjects:
R Medicine (General)
Online Access:http://eprints.um.edu.my/282/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1368487/?tool=pubmed
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spelling my.um.eprints.2822017-07-14T07:36:08Z http://eprints.um.edu.my/282/ The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes. Sim, S.M. Back, D.J. Breckenridge, A.M. R Medicine (General) 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. Blackwell Publishing 1991-07 Article PeerReviewed Sim, S.M. and Back, D.J. and Breckenridge, A.M. (1991) The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes. British Journal of Clinical Pharmacology, 32 (1). pp. 17-21. ISSN 0306-5251 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1368487/?tool=pubmed 1909542
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic R Medicine (General)
spellingShingle R Medicine (General)
Sim, S.M.
Back, D.J.
Breckenridge, A.M.
The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
description 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.
format Article
author Sim, S.M.
Back, D.J.
Breckenridge, A.M.
author_facet Sim, S.M.
Back, D.J.
Breckenridge, A.M.
author_sort Sim, S.M.
title The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
title_short The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
title_full The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
title_fullStr The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
title_full_unstemmed The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
title_sort effect of various drugs on the glucuronidation of zidovudine (azidothymidine; azt) by human liver microsomes.
publisher Blackwell Publishing
publishDate 1991
url http://eprints.um.edu.my/282/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1368487/?tool=pubmed
_version_ 1643686548045037568
score 13.211869

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