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

Jan Balzarini, Lieve Naesens, S. Aquaro, T. Knispel, C. F. Perno, E. De Clercq, C. Meier

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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 intracellular T( 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 of CycloSal-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.

Original languageEnglish
Pages (from-to)1354-1136
Number of pages219
JournalMolecular Pharmacology
Issue number6
Publication statusPublished - 1999


ASJC Scopus subject areas

  • Pharmacology

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