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).

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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).

Proc Annu Meet Am Assoc Cancer Res; 36:A2211 1995. Unique Identifier : AIDSLINE ICDB/95609986
Mahony WB; Domin BA; Prus KL; Zimmerman TP; Wellcome Research Laboratories, Research Triangle Park, NC 27709

Abstract: 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.

Keywords: Antiviral Agents/PHARMACOLOGY/*PHARMACOKINETICS Cell Line Cell Membrane Permeability/DRUG EFFECTS CD4-Positive T-Lymphocytes/DRUG EFFECTS/*METABOLISM Dideoxynucleosides/PHARMACOLOGY/*PHARMACOKINETICS Erythrocytes/DRUG EFFECTS/*METABOLISM Human HIV/*DRUG EFFECTS Structure-Activity Relationship ABSTRACT
951030
M95A0971

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