The Analytical Chemistry of Anti-AIDS Agents

抗艾滋病药物的分析化学

• 批准号: 6433075
• 负责人: james 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/6433075
• 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 II drug 2'-b-fluoro-2',3'-dideoxyadenosine (F-ddA, lodenosine) and its deaminated anti-HIV-active metabolite 2'-b-fluoro-2',3'-dideoxyinosine (F-ddI) remain the compounds of primary interest. Validated analytical strategies employing reversed-phase HPLC have been used for both the routine and ultrasensitive measurement of F-ddA in HIV-infected human biological fluids. The human metabolism, distribution and pharmacokinetics of oral F-ddA, in both capsule and liquid formulation, have been determined in conjunction with a two-part Phase I clinical trial of this agent in adult AIDS patients. Oral F-ddA given as a component of combination antiretroviral therapy is fully bioequivalent with F-ddA given as monotherapy. Direct fluorogenic derivatization of cellular extracts in conjunction with paired-ion HPLC has been employed for the nonradiochemical measurement of low picomole amounts of intracellular F-ddATP, the active metabolite of both F-ddA and F-ddI. F-ddATP can be measured in periperal blood mononuclear cells from patients treated with F-ddA, but sufficient data is not available to correlate with observed anti-HIV activity. The toxicity, metabolism and biochemical pharmacology of 2'-fluoro-2-deoxyadenosine are under investigation to determine the role of this trace constituent in the toxicity profile of lodenosine. Lipophilic prodrugs of F-ddI activated by adenosine deaminase (ADA) also continue under investigation as potential agents for the treatment of HIV sequestered in the central nervous system (CNS). A physiological pharmacokinetic model has been constructed to study the disposition of selected ADA-activated F-ddI prodrugs by using F-ddA as a model compound. This model is being used to investigate the effects of various physiological and biochemical processes with emphasis on prodrug gastrointestinal absorption, blood-brain-barrier penetration into the CNS, and metabolic activation. Concentration versus time data in plasma and brain following intravenous and oral administration of F-ddA in rats, monkeys and humans are being used for model validation and interspecies scaling. AIDS Title: The Analytical Chemistry of Anti-AIDS Agents

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药代动力学。高性能液相色谱（HPLC）和质谱是强调的技术。 II期药物2'-b-氟-2'，3'-二氧基腺苷（F-DDA，Lodenosine）及其脱氨基抗HIV活性代谢产物2'-b-氟-2'，3'-二羟基氨基胺（F-DDI）仍然是主要利益的化合物。采用反相HPLC的经过验证的分析策略已用于在HIV感染的人类生物流体中对F-DDA的常规和超敏度测量。 在胶囊和液体配方中，口服F-DDA的人类代谢，分布和药代动力学与成人艾滋病患者的两部分I期临床试验结合确定。口服F-DDA作为组合抗逆转录病毒疗法的组成部分是完全生物等效的，F-DDA作为单一疗法。细胞提取物与配对的HPLC结合使用的直接荧光导衍生物已用于对细胞内F-DDATP低脚趾木量的非放射化学测量，这是F-DDA和F-DDI的活性代谢物。 F-DDATP可以在接受F-DDA治疗的患者的外围血液单核细胞中测量，但是足够的数据与观察到的抗HIV活性相关。 正在研究2'-氟-2-脱氧腺苷的毒性，代谢和生化药理学，以确定该痕量成分在洛多尼苷毒性中的作用。腺苷脱氨酶（ADA）激活的F-DDI的亲脂前药也继续研究，作为中枢神经系统（CNS）中HIV治疗的潜在药物。 已经构建了一种生理药代动力学模型，以研究通过使用F-DDA作为模型化合物的选定ADA激活的F-DDI前药的处置。该模型用于研究各种生理和生化过程的影响，重点是胃肠道吸收，血脑屏障渗透到中枢神经系统中以及代谢激活。 在大鼠，猴子和人类静脉内和口服F-DDA后，血浆和大脑中的浓度与时间数据用于模型验证和种间缩放。 艾滋病标题：反辅助代理人的分析化学