title: Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine).
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
authors.forename: T
authors.initials: T
authors.lastname: Knispel
authors.forename: C
authors.initials: C
authors.lastname: Perno
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: C
authors.initials: C
authors.lastname: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism*; D002460:Cell Line; D003470:Culture Media / Q000378:metabolism; D054306:Dideoxynucleotides; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010755:Organophosphates / Q000378:metabolism* / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism; D013942:Thymine Nucleotides / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C113124:2',3'-dideoxy-2',3'-didehydrothymidine monophosphate; D019380:Anti-HIV Agents; D003470:Culture Media; D054306:Dideoxynucleotides; D010755:Organophosphates; D011355:Prodrugs; D013942:Thymine Nucleotides; C401422:cyclosaligenyl 3'-azido-2',3'-dideoxythymidine monophosphate; D014316:Tritium; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine; D018119:Stavudine; D013937:Thymidine Kinase