ANTIRETROVIRUS SPECIFICITY AND INTRACELLULAR METABOLISM OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYTHYMIDINE (STAVUDINE) AND ITS 5'-MONOPHOSPHATE TRIESTER PRODRUG SO324

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.