PT  - JOURNAL ARTICLE
AU  - J Balzarini
AU  - H Egberink
AU  - K Hartmann
AU  - D Cahard
AU  - T Vahlenkamp
AU  - H Thormar
AU  - E De Clercq
AU  - C McGuigan
TI  - Antiretrovirus specificity and intracellular metabolism of 2',3' -didehydro-2',3'-dideoxythymidine (stavudine) and its 5'-monophosphate triester prodrug So324.
DP  - 1996 Nov 01
TA  - Molecular Pharmacology
PG  - 1207--1213
VI  - 50
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/50/5/1207.short
4100  - http://molpharm.aspetjournals.org/content/50/5/1207.full
SO  - Mol Pharmacol1996 Nov 01; 50
AB  - 2',3'-Didehydro-2',3'-dideoxythymidine (d4T) and its lipophilic 5'-monophosphate triester prodrug, So324, were evaluated for their antiretroviral and metabolic properties in four different animal species cell lines. The antiretrovirus activity of So324 was approximately 4-10-fold greater than that of d4T against human immunodeficiency virus types 1 and 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 plexus cells, but 5-fold inferior against murine (Moloney) sarcoma virus in murine embryo fibroblast (C3H) cells. Although the administration of both d4T and So324 resulted in the formation of the 5'-monophosphate (d4T-MP), 5'-diphosphate, and 5'-triphosphate in the different cell lines, 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. Alanyl 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.