RT Journal Article
SR Electronic
T1 Intracellular Metabolism of <em>Cyclo</em>Saligenyl 3′-Azido-2′,3′-dideoxythymidine Monophosphate, a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (Zidovudine)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1354
OP 1361
DO 10.1124/mol.56.6.1354
VO 56
IS 6
A1 Balzarini, Jan
A1 Naesens, Lieve
A1 Aquaro, S.
A1 Knispel, T.
A1 Perno, C.-F.
A1 De Clercq, E.
A1 Meier, C.
YR 1999
UL http://molpharm.aspetjournals.org/content/56/6/1354.abstract
AB The administration of CycloSaligenyl 3′-azido-2′,3′-dideoxythymidine monophosphate (CycloSal-AZTMP) to CEM cells resulted in a concentration- and time-dependent conversion to the 5′-monophosphate (AZTMP), 5′-diphosphate (AZTDP), and 5′-triphosphate (AZTTP) derivatives. High ratios of AZTMP/AZTTP were found in the CEM cell cultures treated with CycloSal-AZTMP. The intracellularT 1/2 of AZTTP in CEM cell cultures treated with either AZT and CycloSal-AZTMP was approximately 3 h. A variety of human T- and B-lymphocyte cell lines efficiently converted the prodrug to the AZT metabolites, whereas peripheral blood lymphocytes and primary monocyte/macrophages showed at least 10-fold lower metabolic conversion of the prodrug.CycloSal-AZTMP failed to generate marked levels of AZT metabolites in thymidine kinase-deficient CEM/TK− cells, an observation that is in agreement with the substantial loss of antiviral activity of CycloSal-AZTMP in CEM/TK− cells. The inability ofCycloSal-AZTMP to generate AZTMP in CEM/TK−cells is presumably due to a relatively high hydrolysis rate of AZTMP to the parent nucleoside AZT, combined with the inability of CEM/TK− cells to phosphorylate AZT to AZTMP through the cytosolic salvage enzyme thymidine kinase.