THE ANALYTICAL CHEMISTRY OF ANTI-AIDS AGENTS

抗艾滋病药物的分析化学

• 批准号: 6160988
• 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/6160988
• 关键词: 2'3' dideoxynucleoside; adenosine deaminase; analytical chemistry; antiAIDS agent; antiviral agents; 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'-b- fluoro-2',3'-dideoxyadenosine (F-ddA) and its deaminated anti-HIV-active metabolite 2'-b-fluoro-2',3'-dideoxyinosine (F-ddI) remain the compounds of primary interest. Analytical strategies employing reversed-phase HPLC have been developed, validated and applied 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 human metabolism, distribution and pharmacokinetics of oral F-ddA is being determined in conjunction with a Phase I clinical trial of this agent in adult AIDS patients. The oral bioavailability of the liquid formulation of F-ddA is high after either fasting (74%)or with food (64%). Preliminary studies indicate that the bioavailability of F-ddA given as capsules is also good (>50%). Lipophilic prodrugs of F-ddI activated by adenosine deaminase also continue under investigation. HPLC methodology for the rapid measurement of F-ddI progrugs such as 6- chloro-2',3'-dideoxypurineriboside and its metabolites in biological fluids and tissues is being developed. Direct fluorogenic derivatization of cellular extracts in conjunction with paired-ion HPLC is being employed for the nonradiochemical measurement of subpicomole amounts of intracellular F-ddATP, the active metabolite of both F-ddA and F-ddI. F-ddATP levels will be measured in periperal blood mononuclear cells from patients treated with F-ddA and correlated with observed anti-HIV activity.

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）和质量 光谱是强调的技术。 I期药物2'-b- Fluoro-2'，3'-脱氧腺苷（F-DDA）及其脱离抗HIV活性 代谢产物2'-b-fluoro-2'，3'-二维氨酸（F-DDI）是化合物 主要兴趣。采用反相HPLC的分析策略 已经开发，验证并适用于例程和 HIV感染的人类生物学中F-DDA的超敏度测量 流体。荧光荧光分析和HPLC分析 检测可以测量血浆中纳摩尔水平的F-DDA。这 口服F-DDA的人类代谢，分布和药代动力学是 与此期间的I临床试验结合确定 成人艾滋病患者的代理。液体的口服生物利用度 禁食后F-DDA的配方很高（74％）或食物 （64％）。初步研究表明F-DDA的生物利用度 作为胶囊也很好（> 50％）。 F-DDI的亲脂前药 腺苷脱氨酶激活也在继续研究中。 HPLC 快速测量F-DDI促进剂的方法，例如6- Chloro-2'，3'-二氧化氧化磷脂及其代谢物在生物学中 流体和组织正在发展。直接荧光衍生化 与配对的HPLC结合使用的细胞提取物是 用于非放射化学测量值 细胞内F-DDATP，F-DDA和F-DDI的活性代谢产物。 F-DDATP水平将在周围血液单核细胞中进行测量 来自用F-DDA治疗并与观察到的抗HIV相关的患者 活动。