HEPATIC FORMATION AND HANDLING OF DRUG METABOLITES

药物代谢物的肝脏形成和处理

• 批准号: 2179234
• 负责人: KIM-CHING S PANG
• 金额: $ 17.39万
• 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 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2179234
• 关键词: acetaminophen; benzoates; biotransformation; chemical conjugate; drug metabolism; erythrocytes; estrone; glucuronides; glutathione; high performance liquid chromatography; indicator dilution test; laboratory rat; liver circulation; liver metabolism; morphine; perfusion; phenylamide; radiotracer; salicylate; sulfates; sulfation; tritium; vascular endothelium permeability

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 metabolizing organ. Methods for probing zonal metabolic heterogeneities: single pass prograde [P, inflow into portal vein (PV)] and retrograde [R, inflow into hepatic vein (HV)] and hepatic artery-portal vein, hepatic artery-hepatic vein [HAPV-HAHV, dual inflow system with substrates given to HA] perfusion and the multiple indicator dilution (MID) technique will be used to examine mechanisms of elimination and transport across hepatocyte membranes for several precursor-metabolite pairs. An injection of a mixture of vascular [51Cr-labeled red blood cells, 125I-labeled albumin, 58CoEDTA (similar to [14C]sucrose)] and cellular (D2O) reference noneliminated indicators and 14C- and 3H-labeled precursor and product will be given, during steady-state bulk perfusion by PR or HAPV-HAHV. The outflow profiles thus obtained will be appropriately analyzed and referenced with respect to the noneliminated reference indicators. Modeling is able to account for the binding effects due to red cells, plasma, or tissue proteins, provide the physiological volumes and the influx, efflux, and sequestration coefficients for both precursor and metabolite, and identify the rate-controlling step. For Aim 1, the hepatic processing of benzoic acid, hippuric acid, taurolithocholic acid 3- sulfate, tracer salicylamide and phenacetin, morphine, morphine-3beta- and 6beta- glucuronides, 4-methyl-umbelliferone (4MU), 4MU glucuronide, harmol, harmol sulfate and glucuronide conjugates, estrone sulfate, estrone, and estradiol (with and without inhibitors of sulfation/desulfation) will be examined. The sulfate conjugate of the bile acid, and of estrone, 4-MU or harmol will be given simultaneously to test for interactions in transport and removal. For Aim 2, the micro-mixing of the hepatic artery and portal vein will be investigated with a full set of noneliminated references with HA or PV injections, then with HA or PV infusion of carrier-mediated [bromosulfophthalein (BSP) and its glutathione conjugate (BSP-GSH)] and flow-limited (salicylamide) substrates at varying HA:PV flow ratios. Events underlying single, parallel, and sequential pathways, futile cycling, enzyme zonation, and competition in uptake will be provided in the above studies. The permeability of the peribiliary capillary plexus to solutes and the potential reduction in liver mass with the probes infused into the HA will be delineated. These studies should lend important insight into mechanisms of drug-metabolite processing of pharmacologically important sulfate and glucuronide conjugates, and differences in preformed vs. generated metabolite removal due to the differing origins.

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 代谢器官 探测区域代谢不均一性的方法： 单向分流[P，流入门静脉（PV）]和逆行[R， 流入肝静脉（HV）]和肝动脉-门静脉，肝 动脉-肝静脉[HAPV-HAHV，双流入系统，给予底物 到HA]灌注和多重指示剂稀释（MID）技术将 用于检查消除和跨 肝细胞膜上的几个代谢物-代谢物对。注射 血管[51 Cr标记的红细胞，125 I标记的 白蛋白，58 CoEDTA（类似于[14 C]蔗糖）]和细胞（D2 O）参比品 未消除的指示剂和14 C和3 H标记的前体和产物 将在PR或HAPV-HAHV的稳态大量灌注期间给予。的 将对由此获得的流出剖面进行适当分析， 参考未消除的参考指示符。 建模能够解释红细胞的结合效应， 血浆或组织蛋白提供生理体积， 流入，流出和螯合系数的前体和 代谢产物，并确定速率控制步骤。对于目标1，肝脏 苯甲酸、马尿酸、牛磺石胆酸3- 硫酸盐、示踪剂水杨酰胺和非那西丁、吗啡、吗啡-3 β-和 6 β-葡糖苷酸，4-甲基伞形酮（4 MU），4 MU葡糖苷酸， 骆驼蓬酚，硫酸骆驼蓬酚和葡糖苷酸缀合物，硫酸雌酮， 雌酮和雌二醇（有和没有抑制剂， 硫酸化/硫酸化）将被检查。胆汁的硫酸盐结合物 酸，雌酮，4-MU或骆驼蓬酚将同时给予测试 在运输和移除过程中的相互作用。对于目标2， 肝动脉和门静脉将用一整套 HA或PV进样的未消除参比品，然后HA或PV进样 载体介导溴磺酞（BSP）输注及其 谷胱甘肽结合物（BSP-GSH）]和限流（水杨酰胺） 在不同的HA：PV流量比的基板。 事件背后的单一， 平行和顺序途径，无效循环，酶区带， 上述研究将提供吸收方面的竞争情况。 的 胆管周围毛细血管丛对溶质的渗透性， 将探针注入HA后， 被描绘出来。这些研究应该提供重要的洞察机制 重要硫酸盐的药物代谢物处理， 葡萄糖醛酸苷缀合物，以及预形成与生成的差异 由于来源不同，代谢物的去除。