TY - JOUR 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 SP - 1354 LP - 1361 DO - 10.1124/mol.56.6.1354 VL - 56 IS - 6 AU - Jan Balzarini AU - Lieve Naesens AU - S. Aquaro AU - T. Knispel AU - C.-F. Perno AU - E. De Clercq AU - C. Meier Y1 - 1999/12/01 UR - http://molpharm.aspetjournals.org/content/56/6/1354.abstract N2 - 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. ER -