The overall objective of this proposal is to investigate the in vitro metabolism of AZT with the long term goal to improve and enhance the therapeutic index of Zidovudine (3-azido-3' deoxythymidine, AZT, Retrovir) for the treatment of the Acquired Immune Deficiency Syndrome (AIDS) and AIDS Related Complex (ARC). AZT is rapidly metabolized by glucuronidation requiring frequent administration and is difficult to maintain constant levels of active drug. The hypothesis being tested is that drugs and/or other agents that interfere with hepatic glucuronidation may prolong the half life of biologically active AZT. The key points being tested are: 1. Specific interaction of therapeutic agents with AZT can be qualitatively and quantiatively elucidated in Hep G2 cell culture. 2. The identification of useful therapeutic agents that decrease AZT glucuronidation leading to improved therapeutic regimens for the treatment of AIDS and ARC. Specifically: a) Lower steady state plasma concentrations of drug can provide greater therapeutic effect with les bone marrow toxicity. b) Reduction of total drug dosage by the oral route may reduce GI and liver toxicity.
