HEPATIC FORMATION AND HANDLING OF DRUG METABOLITES

这项研究提案的长期目标是提供一个彻底的 理解与药物相关的时空变化 主要药物在肝脏中的消失和代谢物形成 生物转化器官。地带性代谢的探测方法 异质性：正常-逆行灌注(NR)和肝动脉- 门静脉、肝动脉-肝静脉(HAPV-HAHV)一次通过大鼠肝脏 将使用灌流和多指示剂稀释技术 研究肝细胞的清除和转运机制 几种前体-代谢物对的膜。在注射后 血管混合物(~(51)铬标记红细胞，~(125)I标记红细胞) 白蛋白，58Co-EDTA，其行为类似于14C-蔗糖)和细胞 (D2O)标记和~(14)C和~3H标记的前体和产物在稳定的- NR(门静脉或肝静脉)和HAPV-HAHV状态整体灌流 (底物注入肝动脉)，一套指示剂稀释度 得到了流出剖面图。生理量和人流量， 前体和代谢物的外排和封存系数可为 经过适当的建模方法后得到。具体地说，肝脏 对乙酰氨基酚-对乙酰氨基酚硫酸盐、水杨酰胺的加工 硫酸水杨酰胺，依那普利-依那普利拉，吗啡-葡萄糖醛酸吗啡， 4-甲基伞形酮-4-甲基伞形花环联合物和三尖杉酯-三尖杉酯 结合物(含和不含去共轭抑制剂、亚硫酸钠、D- 糖-1-4-内酯或D-葡糖内酯)将被研究，因为这些 代表简单的(一步、两步和并行)生物转化 小路。此外，肝动脉在肝药和肝移植中的作用 代谢产物的处理将用活体显微镜进行研究，14C- 非那西丁和~3H-对乙酰氨基酚的提取数据及提取技术 多指标稀释，当门静脉/肝动脉血流时 比例会发生变化。这些结果应该会为我们提供重要的见解 药物代谢产物的加工机制，不同的命运 代谢产物，当在细胞内产生时或当给药到 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。这部作品 还将解释药物中涉及的前体-产品关系- 代谢物介导毒性/活性并改进前药的设计。

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.