| Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. | |
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MedLine Citation:
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PMID: 9660989 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Zidovudine (3'-azido-3'-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were > 100 and 8 micrograms/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 micrograms/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 micrograms/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies. |
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Authors:
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C B Trapnell; R W Klecker; C Jamis-Dow; J M Collins |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Antimicrobial agents and chemotherapy Volume: 42 ISSN: 0066-4804 ISO Abbreviation: Antimicrob. Agents Chemother. Publication Date: 1998 Jul |
Date Detail:
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Created Date: 1998-10-08 Completed Date: 1998-10-08 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 0315061 Medline TA: Antimicrob Agents Chemother Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1592-6 Citation Subset: IM; X |
Affiliation:
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Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA. trapnelc@globomax.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anti-HIV Agents
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metabolism* Anticonvulsants / pharmacology Antifungal Agents / pharmacology Atovaquone Drug Interactions Fluconazole / pharmacology Glucuronates / metabolism Humans Methadone / pharmacology Microsomes, Liver / drug effects, metabolism* Naphthoquinones / pharmacology Narcotics / pharmacology Valproic Acid / pharmacology Zidovudine / metabolism, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Anti-HIV Agents; 0/Anticonvulsants; 0/Antifungal Agents; 0/Glucuronates; 0/Naphthoquinones; 0/Narcotics; 30516-87-1/Zidovudine; 76-99-3/Methadone; 86386-73-4/Fluconazole; 94015-53-9/Atovaquone; 99-66-1/Valproic Acid |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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