ANTIRETROVIRUS SPECIFICITY AND INTRACELLULAR METABOLISM OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYTHYMIDINE (STAVUDINE) AND ITS 5'-MONOPHOSPHATE TRIESTER PRODRUG SO324
J. Balzarini et al., ANTIRETROVIRUS SPECIFICITY AND INTRACELLULAR METABOLISM OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYTHYMIDINE (STAVUDINE) AND ITS 5'-MONOPHOSPHATE TRIESTER PRODRUG SO324, Molecular pharmacology, 50(5), 1996, pp. 1207-1213
2',3'-Didehydro-2',3'-dideoxythymidine (d4T) and its lipophilic 5'-mon
ophosphate triester prodrug, So324, were evaluated for their antiretro
viral and metabolic properties in four different animal species cell l
ines. The antiretrovirus activity of So324 was similar to 4-10-fold gr
eater than that of d4T against human immunodeficiency virus types 1 an
d 2 and simian immunodeficiency virus in human T lymphocyte CEM and MT
-4 cells and against feline immunodeficiency virus in feline Crandell
kidney cells, 50-fold greater against visna virus in sheep choroid ple
xus cells, but 5-fold inferior against murine (Moloney) sarcoma virus
in murine embryo fibroblast (C3H) cells. Although the administration o
f both d4T and So324 resulted in the formation of the 5'-monophosphate
(d4T-MP), 5'-diphosphate, and 5'-triphosphate in the different cell l
ines, a new d4T metabolite markedly accumulated in So324-treated cells
and exceeded d4T-TP levels by 13-242-fold depending on the cell line
used. This metabolite could be identified as alaninyl d4T-MP. Alaninyl
d4T-MP may be considered to be an intracellular depot form of d4T and
/or d4T-MP, which may account for the superior antiretroviral activity
of the lipophilic d4T-MP triester So324 compared with d4T.