THE ANALYTICAL CHEMISTRY OF ANTI-AIDS AGENTS

本项目的目标是研究和开发适用于 分析方法：(1)建立结构和纯度 潜在的抗艾滋病药物和新型抗病毒药物，(2)确定 物理、化学和生化性质，包括辛醇-水 这些化合物及其代谢物的分配系数，以及(3) 在生物样本中测量这些药物及其代谢物以 阐明药理并测定药代动力学。高- 重点介绍了高效液相色谱和质谱学。 技巧。含糖双脱氧核苷，包括2‘-F-Dda和 前药2‘-F-DDI和2’-F-DDG是目前主要的化合物 利息。腺苷脱氨酶在前药激活中的作用也是 正在调查中。同时测定2‘-F-Dda和2’-F-Dda的高效液相色谱方法 血浆、尿液和脑脊液中的F-DDI已被用于 小口径高效液相色谱仪。该方法已应用于血清浓度的测定。 HU-PBL-SCID小鼠慢性灌胃给药后，测定峰值 大鼠团注给药后的血浆浓度，并对中枢神经系统进行研究 在大鼠体内的系统渗透性。2‘-F-Dda体内分解代谢较少 比它的非氟化类似物和增强的血浆暴露 当量剂量。

The objective of this project is the research and development of suitable analytical methods to: (1) establish the structure and purity of potential anti-AIDS agents and new antiviral drugs, (2) determine physical, chemical and biochemical properties, including octanol-water partition coefficients, of these compounds and their metabolites, and (3) measure these drugs and their metabolites in biological samples to elucidate pharmacology and to determine pharmacokinetics. High- performance liquid chromatography and mass spectrometry are emphasized techniques. Sugar-fluorinated dideoxynucleosides, including 2'-F-ddA and prodrugs of 2'-F-ddI and 2'-F-ddG are currently the compounds of primary interest. The role of adenosine deaminase in prodrug activation is also under investigation. An HPLC method for measuring both 2'-F-ddA and 2'- F-ddI in plasma, urine and cerebrospinal fluid has been adapted for narrow-bore HPLC. This method has been applied to determine serum levels in Hu-PBL-SCID mice after chronic oral administration, to measure peak plasma levels in rats after bolus dosing, and to study central nervous system penetration in rats. 2'-F-ddA exhibits less catabolism in vivo than its non-fluorinated analogue and enhanced plasma exposure for an equivalent dose.