| 3{dollar}spprime{dollar}Azido-3{dollar}spprime{dollar}-deoxythymidine (AZT) currently represents the first-line agent in the treatment of AIDS and AIDS-related complex. Its use, however, is limited by severe bone marrow suppression. Although 40% of orally administered AZT is lost due to extensive first-pass catabolism by the liver, detailed knowledge about AZT catabolism is limited. The primary focus of this dissertation is to gain a better understanding of the AZT pharmacology with emphasis on its catabolic disposition.; AZT catabolism was examined both in vitro and in vivo. Using liver microsomes, AZT was shown to have a lower Km and a 5- to 6-fold higher catalytic efficiency for human UDP-glucuronyl-transferase (UDPGT) when compared to rat UDPGT. However, in intact rat liver cells, extensive formation of GAZT was observed. In addition, substantial amounts of two previously unidentified catabolites, 3{dollar}spprime{dollar}-amino-3{dollar}spprime{dollar}-deoxythymidine (AMT) and its glucuronide, GAMT, were also detected. Furthermore, AMT was shown to be approximately 5- to 7-fold more toxic to human bone marrow cells in vitro than AZT, suggesting that AMT may have a role in AZT induced myelotoxicity. Using other 3{dollar}spprime{dollar}-azido substituted nucleosides, reduction to a 3{dollar}spprime{dollar}-amino derivative was shown to be a general catabolic pathway for these compounds.; To determine the importance of AZT reduction, in vivo formation of AMT was evaluated in rhesus monkeys. Following subcutaneous administration of AZT, substantial levels of AMT were detected in biological fluids (plasma, urine, CSF). Co-administration of probenecid with AZT lead to enhancement of AMT formation both in vivo and in vitro. These observations prompted the investigation of AMT formation in humans. Following intravenous administration of AZT, substantial levels of AMT were detected in plasma and urine. The substantial amount of AMT formed in patients suggests that AMT may affect the pharmacodynamic properties of AZT. |
