Intracellular metabolism of <i>Cyclo</i>Saligenyl 3′-azido-2′,3′-dideoxythymidine monophosphate, a prodrug of 3′-azido-2′,3′-dideoxythymidine (zidovudine)

作     者：Balzarini, J Naesens, L Aquaro, S Knispel, T Perno, CF De Clercq, E Meier, C 

作者机构：Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium Univ Roma Tor Vergata Dept Expt Med Rome Italy Univ Hamburg Inst Organ Chem D-2000 Hamburg Germany IRCCS Rome Italy 

出 版 物：《MOLECULAR PHARMACOLOGY》 (分子药理学)

年 卷 期：1999年第56卷第6期

页      面：1354-1361页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：抗HIV药/代谢 细胞系 培养基/代谢 双脱氧核苷酸类 药物稳定性 氢离子浓度 药物前体/代谢 药物前体/药理学 司他夫定/类似物和衍生物 司他夫定/代谢 胸苷激酶/代谢 胸腺嘧啶核苷酸类/代谢 氚 肿瘤细胞 培养的 齐多夫定/类似物和衍生物 齐多夫定/代谢 齐多夫定/药理学 人类 

摘      要：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.