Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes : relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid

摘要: Zidovudine (3′-azido-3′-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to 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 inhibition. The effect these drugs on AZT glucuronidation was assessed vitro by using hepatic microsomes begin understanding vitro-in vivo correlations for metabolism. concentrations drug studied were equal those reported with usual doses at least 10 times higher than would be expected doses. High-performance liquid chromatography used assess respective metabolism formation GAZT. All four exhibited concentration-dependent inhibition glucuronidation. atovaquone methadone which caused 50% >100 8 μg/ml, well above their concentrations. Fluconazole 50 100 are within ranges respectively. These data suggest may more clinically significant concomitant fluconazole acid. Factors such inter- intraindividual pharmacokinetic variability changes intracellular should considered other mechanisms responsible pharmacokinetics therapies.