MEMBRANE PERMEATION MECHANISMS OF 2'-DIDEOXYNUCLEOSIDES,3'-DIDEOXYNUCLEOSIDES

The mechanism of membrane permeation of several 2',3'-dideoxynucleosid es was investigated at 37-degrees with human erythrocyles using an ''i nhibitor-stop'' assay. Transport (per 5 muL cells) via the nucleoside and nucleobase carriers was assessed by inhibition of influx with dila zep and adenine, respectively. Mechanisms of cellular entry were highl y individualized: 2',3'-dideoxyadenosine and 3'-deoxythymidin-2'-ene v ia nonfacilitated diffusion, with high rates; 2',3'-dideoxyguanosine m ainly via the nucleobase carrier (K(m) = 390 muM, V(max) = 32 pmol/sec ); 2',3'-dideoxyinosine by both nucleobase (K(m) = 850 muM, V(max) = 2 .7 pmol/sec) and nucleoside (K(m) = 7.4 mM, V(max) = 16 pmol/sec) carr iers, with a low rate of nonfacilitated diffusion; and 2',3'-dideoxycy tidine, equally by the nuclcoside carrier (K(m) = 23 mM, V(max) = 65 p mol/sec) and by nonfacilitated diffusion, with a low rate. These resul ts demonstrate that the nucleobase carrier plays an important role in the influx of two of these dideoxynucleosides and that nonfacilitated diffusion is not necessarily the chief mode of membrane permeation of this class of drugs.