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'-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.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
Egberink
H
H
Hartmann
K
K
Cahard
D
D
Vahlenkamp
T
T
Thormar
H
H
De Clercq
E
E
McGuigan
C
C
D016475:3T3 Cells / Q000821:virology; D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D002415:Cats; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology*; D012190:Retroviridae / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012680:Sensitivity and Specificity; D018119:Stavudine / Q000378:metabolism* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000998:Antiviral Agents; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; C100595:So 324; D013938:Thymidine Monophosphate; D018119:Stavudine; D000409:Alanine