Document 0249
 DOCN  M9550249
 TI    Effects of dideoxyinosine and dideoxycytidine on the intracellular
       phosphorylation of zidovudine in human mononuclear cells.
 DT    9505
 AU    Veal GJ; Wild MJ; Barry MG; Back DJ; Department of Pharmacology and
       Therapeutics, University of; Liverpool.
 SO    Br J Clin Pharmacol. 1994 Oct;38(4):323-8. Unique Identifier : AIDSLINE
       MED/95134619
 AB    1. Zidovudine (3'-azido-2',3'-dideoxythymidine; AZT; ZDV) is a
       dideoxynucleoside analogue active against human immunodeficiency virus
       (HIV). We are currently investigating the intracellular metabolism of
       ZDV to its putative active triphosphate form (ZDV triphosphate) in
       peripheral blood mononuclear cells and a lymphoblastoid cell line
       (h1A2v2). 2. Optimal conditions for intracellular phosphate formation in
       peripheral blood mononuclear cells occurred following a 72 h
       preincubation with the mitogen phytohaemagglutinin at a concentration of
       10 micrograms ml-1. ZDV was metabolized predominantly to the
       monophosphate with smaller amounts of the di- and triphosphate
       anabolites. There was considerable inter- and intraindividual
       variability in phosphate formation in peripheral blood mononuclear
       cells. A similar pattern of phosphorylation was seen with the h1A2v2
       lymphoblastoid cell line with ZDV monophosphate being the major
       metabolite. 3. With increasing interest in combination nucleoside
       analogue therapy in HIV-positive patients it is important to know if an
       interaction occurs at the level of phosphorylation. Neither
       dideoxyinosine (ddI) or dideoxycytidine (ddC) significantly reduced the
       intracellular phosphorylation of ZDV in either peripheral blood
       mononuclear cells or h1A2v2 cells. In contrast thymidine always gave
       marked inhibition (e.g. at 2.0 microM, 89% inhibition of total phosphate
       formation in peripheral blood mononuclear cells and 79% in h1A2v2
       cells). It is, therefore, unlikely that in vivo either ddI or ddC will
       perturb ZDV phosphorylation.
 DE    Analysis of Variance  B-Lymphocytes/CYTOLOGY/DRUG EFFECTS  Cell Line
       Cells, Cultured  Didanosine/*PHARMACOLOGY  Drug Interactions  Human
       Leukocytes, Mononuclear/*DRUG EFFECTS  Lymphocyte Transformation
       Phosphorylation/DRUG EFFECTS  Phytohemagglutinins/PHARMACOLOGY  Support,
       Non-U.S. Gov't  Thymidine/PHARMACOLOGY  Zalcitabine/*PHARMACOLOGY
       Zidovudine/*METABOLISM  JOURNAL ARTICLE

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