PT  - JOURNAL ARTICLE
AU  - Balzarini, Jan
AU  - Naesens, Lieve
AU  - Aquaro, S.
AU  - Knispel, T.
AU  - Perno, C.-F.
AU  - De Clercq, E.
AU  - Meier, C.
TI  - Intracellular Metabolism of <em>Cyclo</em>Saligenyl 3′-Azido-2′,3′-dideoxythymidine Monophosphate, a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (Zidovudine)
AID  - 10.1124/mol.56.6.1354
DP  - 1999 Dec 01
TA  - Molecular Pharmacology
PG  - 1354--1361
VI  - 56
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/56/6/1354.short
4100  - http://molpharm.aspetjournals.org/content/56/6/1354.full
SO  - Mol Pharmacol1999 Dec 01; 56
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.