IN-VITRO METABOLISM OF ZIDOVUDINE (AZT) I N HUMAN

The metabolism of zidovudine (AZT) and its modulating factors have bee n studied in human liver microsomes. In a first step, we demonstrated the involvement of UDP-glucuronosyltransferase (UDPGT) 2 form in AZT g lucuronidation. In a second step, in order to predict drug interaction s, we screened the effect of 52 drugs, representative of 17 different therapeutic classes, on AZT glucuronidation. We demonstrated that abou t twenty molecules glucuronidated or not are able to inhibit AZT glucu ronidation. Finally, the NADPH-dependent reductive metabolism of AZT w hich produced a toxic metabolite, 3'-amino-3'-deoxythymidine (AMT) has been studied. Our studies demonstrated that AMT was formed only under anaerobic conditions and that its formation is catalysed by the NADPH -cytochrome P450 reductase.