THE ANALYTICAL CHEMISTRY OF ANTI-AIDS AGENTS

抗艾滋病药物的分析化学

• 批准号: 2463714
• 负责人: J A KELLEY
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2463714
• 关键词: 2'3' dideoxynucleoside; adenosine deaminase; analytical chemistry; antiAIDS agent; antiviral agents; clinical research; drug design /synthesis /production; drug metabolism; fluorine; halogenation; high performance liquid chromatography; human tissue; laboratory rat; mass spectrometry; method development; pharmacokinetics; prodrugs

The objective of this project is the research and development of suitable bioanalytical methods to: (1) establish the structure and purity of potential anti-AIDS agents and new antiviral drugs, (2) determine the 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 (HPLC) and mass spectrometry are the emphasized techniques. The Phase I drug 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) and its deaminated anti-HIV-active metabolite 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI) remain the compounds of primary interest. Analytical strategies employing reversed-phase HPLC have been developed and validated for both the routine and ultrasensitive measurement of F-ddA in HIV-infected human biological fluids. Fluorogenic derivatization and HPLC analysis with fluorescence detection allow measurement of F-ddA at nanomolar levels in plasma. The metabolism, distribution and pharmacokinetics of F-ddA is under investigation following intravenous and oral administration during a Phase I clinical trial of this agent in AIDS patients. Preliminary results indicate that the bioavailability of oral F-ddA is good (>50%). Lipophilic prodrugs of F-ddI activated by adenosine deaminase also continue under investigation. HPLC methodology for the measurement of 6-chloro-2',3'-dideoxypurineriboside in biological fluids and tissues has been developed and applied to show enhancement of central nervous system penetration of F-ddI in rats after administration of this prodrug. Direct fluorogenic derivatization of cellular extracts in conjunction with paired-ion HPLC has been employed for the nonradiochemical measurement of subpicomole amounts of intracellular F-ddATP, the active metabolite of both F-ddA and F-ddI.

该项目的目的是研究和发展 合适的生物分析方法：（1）建立结构和 潜在的抗AID剂和新抗病毒药的纯度，（2） 确定物理，化学和生化特性，包括 这些化合物的辛醇 - 水分区系数及其 代谢产物，（3）测量这些药物及其代谢物 生物样品以阐明药理学并确定 药代动力学。 高性能液相色谱（HPLC）和 质谱是强调的技术。 第一期药物 2'-beta-fluoro-2'，3'-二氧化腺苷（F-dda）及其脱水 抗HIV活性代谢物2'-beta-fluoro-2'，3'-二氧氨基氨酸（F-DDI） 仍然是主要兴趣的化合物。 分析策略 采用反相HPLC已开发和验证 F-DDA的常规测量和超敏度测量 HIV感染的人类生物流体。荧光衍生化和 荧光检测的HPLC分析允许测量F-DDA 在等离子体中的纳摩尔水平。 新陈代谢，分布和 静脉注射后，F-DDA的药代动力学正在研究 和在该药物的I期临床试验中进行口服给药 在艾滋病患者中。 初步结果表明 口服F-DDA的生物利用度很好（> 50％）。 亲脂的前药 腺苷脱氨酶激活的F-DDI也在 调查。 HPLC方法的测量方法 在生物液和组织中的6-氯-2'，3'-二氧化氧化 已开发并应用以显示中枢神经的增强 给药后，F-DDI在大鼠中的系统渗透 前药。 细胞提取物中的直接荧光衍生化 与配对的HPLC结合已使用 亚细胞内数量的非放射化学测量 F-DDATP，F-DDA和F-DDI的活性代谢产物。