HEPATIC FORMATION AND HANDLING OF DRUG METABOLITES

药物代谢物的肝脏形成和处理

• 批准号: 3294489
• 负责人: KIM-CHING S PANG
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 1994-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3294489
• 关键词: acetaminophen; alpha benzopyrone; biotransformation; carbon; drug metabolism; enalapril; glucuronides; high performance liquid chromatography; indicator dilution test; iodine; laboratory rat; liver circulation; liver function; liver metabolism; liver pharmacology; morphine; perfusion; phenylamide; radionuclides; radiotracer; salicylate; sulfates; sulfur; toxin metabolism; tritium

The long-term goal of the research proposal is to provide a thorough understanding of the space- and time-related changes associated with drug disappearance and metabolite formation in the liver, the major drug biotransformation organ. Methods for probing zonal metabolic heterogeneities: normal-retrograde (NR) perfusion and hepatic artery- portal vein, hepatic artery-hepatic vein (HAPV-HAHV) once-through rat liver perfusions, and the technique of multiple indicator dilution will be used to examine mechanisms of elimination and transport across hepatocyte membranes for several precursor-metabolite pairs. Following an injection of a mixture of vascular (51Cr-labeled red blood cells, 125I-labeled albumin, 58Co-EDTA which behaves similarly as 14C-sucrose) and cellular (D2O) markers and 14C- and 3H-labeled precursor and product during steady- state bulk perfusion by NR (portal or hepatic vein) and HAPV-HAHV (substrate and injection into hepatic artery), a set of indicator dilution outflow profiles are obtained. The physiological volumes, and the influx, efflux, and sequestration coefficients for precursor and metabolite may be obtained after appropriate modeling approaches. Specifically, the hepatic processing of acetaminophen-acetaminophen sulfate, salicylamide- salicylamide sulfate, enalapril-enalaprilat, morphine-morphine glucuronide, 4-methylumbelliferone-4-methylumbelliferyl conjugates and harmol-harmol conjugates (with and without deconjugation inhibitors, sodium sulfite, D- saccharo-1-4-lactone or D-glucarolactone) will be studied, as these represent simple (one step, two steps, and parallel) biotransformation pathways. Moreover, the role of the hepatic artery in hepatic drug and metabolite processing will be investigated with intravital microscopy, 14C- phenacetin and 3H-acetaminophen extraction data, and the technique of multiple indicator dilution, when the portal vein/hepatic artery flow ratios are altered. The results should lend important insights into mechanisms of drug-metabolite processing, the differential fates of metabolites, when generated intracellularly or when administered into the organ, due to the differing points of origin, reversible-futile metabolism, and on the role of the hepatic artery in hepatic metabolism. This work will also explain precursor-product relationships involved in drug- metabolite mediated toxicity/activity and improve the designs of prodrugs.

该研究提案的长期目标是提供一个全面的 了解与药物相关的空间和时间相关变化 肝脏中的主要药物消失和代谢产物形成 生物转化器官 探测区域代谢的方法 异质性：正常-逆行（NR）灌注和肝动脉- 门静脉、肝动脉-肝静脉（HAPV-HAHV）一次通过大鼠肝脏 灌注，并将使用多种指示剂稀释技术 检查清除和跨肝细胞转运的机制 几个代谢物-代谢物对。 在注射之后 血管（51 Cr标记的红细胞、125 I标记的红细胞）混合物 白蛋白，58 Co-EDTA，其行为类似于14 C-蔗糖）和细胞 (D2O)标记物和14 C和3 H标记的前体和产物， 通过NR（门静脉或肝静脉）和HAPV-HAHV进行状态整体灌注 （底物和注入肝动脉），一组指示剂稀释液 获得流出轮廓。 生理量，和流入量， 前体和代谢物的流出和螯合系数可以 经过适当的建模方法。 特别是肝脏 对乙酰氨基酚-对乙酰氨基酚硫酸盐、水杨酰胺- 硫酸水杨酰胺，依那普利-依那普利拉，吗啡-吗啡葡糖苷酸， 4-甲基伞形酮-4-甲基伞形酮基缀合物和哈尔酚-哈尔酚 偶联物（有和没有去偶联抑制剂，亚硫酸钠，D- 糖-1-4-内酯或D-葡糖醛酸内酯），因为这些 代表简单（一步、两步和平行）生物转化 路径。 此外，肝动脉在肝脏药物和 代谢物处理将采用活体显微镜进行研究，14 C- 非那西丁和3 H-对乙酰氨基酚提取数据，以及 多指标稀释，当门静脉/肝动脉血流 比例发生了变化。 这些结果应该能为我们提供重要的见解， 药物代谢物加工的机制， 代谢物，当在细胞内产生时或当施用到细胞内时， 器官，由于起源点不同，可逆-无效代谢， 以及肝动脉在肝脏代谢中的作用。 这项工作 还将解释涉及药物的药物-产品关系， 代谢物介导的毒性/活性，并改善前药的设计。