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 Macaca nemestrina has been shown to be a suitable animal model for use in the study of the disposition of AZT. However, since AZT is activated 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 human volunteers. At 5 microM extracellular AZT, both human and macaque PBMCs rapidly convert AZT to AZT monophosphate (AZTMP) (84% of total phosphorylated 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 microM. Similar 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 fivefold increase in intracellular AZT and AZTMP levels and a twofold increase in AZTDP and AZTTP levels (picomoles per 10(7) cells) when compared with those in the uninfected cells (at 4 h with 0.9 microM extracellular concentration). This increase in AZT metabolite levels has also been reported for human immunodeficiency virus-infected PBMCs. Collectively, 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 effect the in vivo phosphorylation of AZT.
Qian
M
M
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Chandrasena
G
G
Ho
R J
RJ
Unadkat
J D
JD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000097:blood; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008254:Macaca nemestrina; D010766:Phosphorylation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood; D015215:Zidovudine / Q000378:metabolism*
D015215:Zidovudine