COMPARISON OF RATES OF INTRACELLULAR METABOLISM OF ZIDOVUDINE IN HUMAN AND PRIMATE PERIPHERAL-BLOOD MONONUCLEAR-CELLS

3'-Azido-3'-deoxythymidine (AZT) is a drug of choice for the treatment of AIDS. On the basis of pharmacokinetic data, the nonhuman primate M acaca nemestrina has been shown to be a suitable animal model for use in the study of the disposition of AZT. However, since AZT is activate d to its metabolite, the AZT triphosphate (AZTTP), intracellularly, we investigated the intracellular activation of AZT in peripheral blood mononuclear cells (PBMCs) of healthy and simian immunodeficiency virus -infected macaques and compared it with that in PBMCs obtained from hu man volunteers. At 5 mu M extracellular AZT, both human and macaque PB MCs rapidly convert AZT to AZT monophosphate (AZTMP) (84% of total pho sphorylated products) in 4 h. Increases in AZTMP levels of 7.7- and 12 -fold were observed in human and macaque PBMCs, respectively, when the extracellular AZT concentration increased from 0.45 to 14.4 mu M. Sim ilar ratios of AZT metabolites, AZT diphosphate (AZTDP)/AZTTP (0.7 to 1.4), AZTMP/AZTDP (3 to 14), and AZTMP/AZTTP (3 to 19), over the same AZT concentration range were observed in both human and macaque PBMCs, suggesting that these cells have similar capacities to phosphorylate AZT. Simian immunodeficiency virus-infected macaque PBMCs showed a fiv efold increase in intracellular AZT and AZTMP levels and a twofold inc rease in AZTDP and AZTTP levels (picomoles per 107 cells) when compare d with those in the uninfected cells (at 4 h with 0.9 mu M extracellul ar concentration). This increase in AZT metabolite levels has also bee n reported for human immunodeficiency virus-infected PBMCs. Collective ly, given the similarities in phosphorylation profiles between healthy and infected human and macaque PBMCs, we conclude that the macaque is a suitable animal model for use in the study of factors that can affe ct the in vivo phosphorylation of AZT.