Document 0970
 DOCN  M95A0970
 TI    Membrane permeation characteristics of the structurally related anti-HIV
       agents 1592U89 and (-)-carbovir in human erythrocytes and human
       T-lymphoblastoid CD4+ CEM cells (Meeting abstract).
 DT    9510
 AU    Mahony WB; Domin BA; Prus KL; Zimmerman TP; Wellcome Research
       Laboratories, Research Triangle Park, NC 27709
 SO    Proc Annu Meet Am Assoc Cancer Res; 36:A2211 1995. Unique Identifier :
       AIDSLINE ICDB/95609986
 AB    1592U89
       ((1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclope-
       ntene-1-methanol) is a carbocyclic guanosine analog that is currently in
       Phase I clinical trials for treatment of human immunodeficiency virus
       infection. Structurally, 1592U89 and (-)-carbovir (CBV) differ only at
       the 6-position of the nucleobase: the 6-cyclopropylamino group of
       1592U89 contrasts with the 6-oxy moiety of CBV. We compared membrane
       permeation characteristics of these two compounds at 20 C both in human
       erythrocytes and in human T-lymphoblastoid CD4+ CEM cells. Initial rates
       of influx were measured using a 'papaverine-stop' assay. In human
       erythrocytes, 1592U89 influx was fast, nonsaturable (rate constant = 220
       pmol/s/mM/ul cell water), and not inhibited by nucleosides or
       nucleobases; CBV influx was slow, saturable (Vmax = 0.67 pmol/s/ul cell
       water, Km = 60 uM), and strongly inhibited by adenine or hypoxanthine.
       Similar qualitative results were seen in CD4+ CEM cells. However, in
       these latter cells, CBV influx rates (Vmax = 2.3 pmol/s/ul cell water Km
       = 75 uM) were faster, and 1592U89 influx rates (rate constant = 28
       pmol/s/mM/ul cell water) were slower, compared to the corresponding
       rates in erythrocytes. Equilibrium studies further revealed that these
       compounds were concentrated intracellularly in both cell types but not
       in erythrocyte ghosts, suggesting cytosolic protein binding of 1592U89
       and CBV following membrane permeation. We conclude that, in both cell
       types, the influx of CBV is relatively slow and primarily dependent on
       the nucleobase carrier, whereas the influx of 1592U89, a more lipophilic
       compound, occurs relatively rapidly by nonfacilitated diffusion.
 DE    Antiviral Agents/PHARMACOLOGY/*PHARMACOKINETICS  CD4-Positive
       T-Lymphocytes/DRUG EFFECTS/*METABOLISM  Cell Line  Cell Membrane
       Permeability/DRUG EFFECTS
       Dideoxynucleosides/PHARMACOLOGY/*PHARMACOKINETICS  Erythrocytes/DRUG
       EFFECTS/*METABOLISM  HIV/*DRUG EFFECTS  Human  Structure-Activity
       Relationship  MEETING ABSTRACT

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