Intracellular metabolism of CycloSaligenyl 3 '-azido-2 ',3 '-dideoxythymidine monophosphate, a prodrug of 3 '-azido-2 ',3 '-dideoxythymidine (zidovudine)

The administration of CycloSaligenyl 3'-azido-2',3'-dideoxythymidine monoph osphate (CycloSal-AZTMP) to CEM cells resulted in a concentration- and time -dependent conversion to the 5'-monophosphate (AZTMP), 5'-diphosphate (AZTD P), and 5'-triphosphate (AZTTP) derivatives. High ratios of AZTMP/AZTTP wer e found in the CEM cell cultures treated with CycloSal-AZTMP. The intracell ular T-1/2 of AZTTP in CEM cell cultures treated with either AZT and CycloS al-AZTMP was approximately 3 h. A variety of human T- and B-lymphocyte cell lines efficiently converted the prodrug to the AZT metabolites, whereas pe ripheral blood lymphocytes and primary monocyte/macrophages showed at least 10-fold lower metabolic conversion of the prodrug. CycloSal-AZTMP failed t o generate marked levels of AZT metabolites in thymidine kinase-deficient C EM/TK- cells, an observation that is in agreement with the substantial loss of antiviral activity of CycloSal-AZTMP in CEM/TK- cells. The inability of CycloSal-AZTMP to generate AZTMP in CEM/TK- cells is presumably due to a r elatively high hydrolysis rate of AZTMP to the parent nucleoside AZT, combi ned with the inability of CEM/TK- cells to phosphorylate AZT to AZTMP throu gh the cytosolic salvage enzyme thymidine kinase.