HEPATIC FORMATION AND HANDLING OF DRUG METABOLITES

药物代谢物的肝脏形成和处理

• 批准号: 3294483
• 负责人: KIM-CHING S PANG
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3294483
• 关键词: acetaminophen; drug metabolism; glucuronides; high performance liquid chromatography; liver pharmacology; morphine; radiotracer; salicylate; sulfates; tritium

We wish to test the hypothesis that hepatic formation of metabolites occurs as a distributed-in-space phenomenon: the sojourns of a locally generated metabolite will differ from that of preformed metabolite due to their differing points of entry into the liver. These differences occur because input as generated metabolite depends on drug uptake and metabolism, and formation of any metabolite from a precursor must precede metabolite elimination. The elimination of metabolite generated from precursor and preformed metabolite will differ despite involvement of the same metabolizing enzyme(s) and processes for transfer across cells. We propose to develop an indepth theoretical treatment of a drug that forms a) a single metabolite which in turn is not further eliminated (metabolized or excreted), b) a single metabolite which is further eliminated, and c) two or more metabolites formed by competing pathways. Experimentally, we wish to study the following substrates and their metabolites in the perfused rat liver preparation: a) 3H- acetaminophen (A) and 3H-salicylamide and their 35S-sulfate conjugates; b) 14C-enalapril and 3H-enalaprilat; 3H-morphine and 14C-morphine glucuronide; 14C-acetanilide and its p-alkoxy analogs to 14C-A and 14C-AS; c) 3H-harmol and 3H-4- methylumbelliferone and their labeled (35S)-sulfates and (14C)- glucuronides (in absence and presence of sulfate inhibitor, DCNP), compounds that will be assayed by TCL and HPLC. While maintaining a single pass liver perfusion with steadystate infusions of unlabeled drug or preformed metabolite (varying levels of input concentrations), a rapid injection of radiolabeled drug and metabolite and vascular reference compounds (51Cr- RBC, 125I-albumin, and 32p-phosphate) will be used to produce a set of multiple indicator dilution curves (MID). The various techniques (normal, retrograde, hepatic artery) of oncethrough perfusion and MID will provide information on underlying processes: red cell and protein binding, influx (barrier-limited, flowlimited, and carrier- or concentrative mechanisms), efflux, and sequestration of drug and metabolite formation as well as the behaviour of preformed metabolite under both linear and nonlinear conditions. The theoretical development and the experimentally-acquired information will further our knowledge on the differences in hepatic handling between a generated vs preformed metabolite, and provide a solid basis for understanding the toxicological/pharmacological differences in generation and processing of drug metabolites.

我们希望检验这一假设，即肝脏形成的 代谢物以空间分布现象出现： 局部产生的代谢物的逗留将不同于 由于它们的不同进入点， 肝脏 这些差异的产生是因为 代谢产物依赖于药物的摄取和代谢， 前体的任何代谢物必须先于代谢物 淘汰 代谢产物的消除 前体和预形成的代谢物将不同， 涉及相同的代谢酶和过程 用于跨细胞转移。 我们建议开发一个深入的 形成a）单一代谢物的药物的理论治疗 其进而不被进一步消除（代谢或排泄）， B）进一步消除的单一代谢物，和 更多的代谢物通过竞争途径形成。 在实验上，我们希望研究以下底物， 它们在灌流大鼠肝脏制备物中的代谢产物：a）3 H- 对乙酰氨基酚（A）和3 H-水杨酰胺及其35 S-硫酸盐 缀合物; B）14 C-依那普利和3 H-依那普利拉; 3 H-吗啡和 14 C-吗啡葡糖苷酸; 14 C-乙酰苯胺及其对位烷氧基 14 C-A和14 C-AS的类似物; c）3 H-骆驼蓬酚和3 H-4- 甲基伞形酮及其标记的（35 S）-硫酸盐和（14 C）- 葡萄糖醛酸苷（在不存在和存在硫酸盐抑制剂DCNP的情况下）， 将通过TCL和HPLC测定的化合物。 而 维持稳态的单程肝脏灌注 输注未标记药物或预形成的代谢物（不同 输入浓度水平），快速注射放射性标记的 药物和代谢物以及血管参比化合物（51 Cr- RBC、125 I-白蛋白和32 P-磷酸盐）将用于生产 多指示剂稀释曲线（MID）。 的各种 技术（正常，逆行，肝动脉）一次通过 灌注和MID将提供有关基础 过程：红细胞和蛋白质结合，流入（屏障限制， 限流和载体或浓缩机制），外排， 以及药物和代谢物形成的隔离， 在线性和非线性条件下， 非线性条件 工作理论发展 实验获得的信息将进一步加深我们的知识 关于生成的与 预形成的代谢物，并提供坚实的基础，了解 世代之间的毒理学/药理学差异， 药物代谢物的加工。