       Document 0010
 DOCN  M9550010
 TI    Comparison of rates of intracellular metabolism of zidovudine in human
       and primate peripheral blood mononuclear cells.
 DT    9505
 AU    Qian M; Chandrasena G; Ho RJ; Unadkat JD; Department of Pharmaceutics,
       School of Pharmacy, University of; Washington, Seattle 98195.
 SO    Antimicrob Agents Chemother. 1994 Oct;38(10):2398-403. Unique Identifier
       : AIDSLINE MED/95142584
 AB    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.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Animal  Comparative Study  Dose-Response Relationship, Drug  Human  HIV
       Infections/BLOOD  Leukocytes, Mononuclear/*METABOLISM  Macaca nemestrina
       Phosphorylation  Simian Acquired Immunodeficiency Syndrome/BLOOD
       Support, U.S. Gov't, P.H.S.  Zidovudine/*METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

