Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: The effect of fluconazole on zidovudine glucuronidation

Verawan Uchaipichat, Leanne K. Winner, Peter I. MacKenzie, David J. Elliot, J. Andrew Williams, John O. Miners

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143 Citations (Scopus)


Aims: Using the fluconazole-zidovudine (AZT) interaction as a model, to determine whether inhibition of UDP-glucuronosyltransferase (UGT) catalysed drug metabolism in vivo could be predicted quantitatively from in vitro kinetic data generated in the presence and absence bovine serum albumin (BSA). Methods: Kinetic constants for AZT glucuronidation were generated using human liver microsomes (HLM) and recombinant UGT2B7, the principal enzyme responsible for AZT glucuronidation, as the enzyme sources with and without fluconazole. K i values were used to estimate the decrease in AZT clearance in vivo. Results: Addition of BSA (2%) to incubations decreased the Km values for AZT glucuronidation by 85-90% for the HLM (923 ± 357 to 91 ± 9 μm) and UGT2B7 (478-70 μm) catalysed reactions, with little effect on Vmax. Fluconazole, which was shown to be a selective inhibitor of UGT2B7, competitively inhibited AZT glucuronidation by HLM and UGT2B7. Like the Km, BSA caused an 87% reduction in the Ki for fluconazole inhibition of AZT glucuronidation by HLM (1133 ± 403 to 145 ± 36 μm) and UGT2B7 (529 to 73 μm). Ki values determined for fluconazole using HLM and UGT2B7 in the presence (but not absence) of BSA predicted an interaction in vivo. The predicted magnitude of the interaction ranged from 41% to 217% of the reported AUC increase in patients, depending on the value of the in vivo fluconazole concentration employed in calculations. Conclusions: Ki values determined under certain experimental conditions may quantitatively predict inhibition of UGT catalysed drug glucuronidation in vivo.

Original languageEnglish
Pages (from-to)427-439
Number of pages13
JournalBritish Journal of Clinical Pharmacology
Issue number4
Publication statusPublished or Issued - Apr 2006


  • Drug interactions
  • Fluconazole
  • Glucoronidation
  • In vitro-in vivo correlation
  • UDP-glucuronosyltransferase
  • Zidovudine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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