INTESTINAL CLEARANCE--MECHANISMS & PLASMA LEVEL EFFECTS

肠道清除——机制

• 批准号: 2701617
• 负责人: DAVID FLEISHER
• 金额: $ 13.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2701617
• 关键词: cimetidine; clearance rate; clinical research; drug interactions; drug metabolism; enzyme substrate; gastrointestinal circulation; gastrointestinal drug absorption; human subject; isozymes; laboratory rat; methionine; nutrient drug interaction; nutrition related tag; oxygenases; perfusion; plasma; species difference; sulfoxide

The long-term objective of the proposed research is to determine the impact of intestinal clearance on drug plasma level variability. In preliminary studies, substantial appearance of the sulfoxide metabolite of a thioether imidazole drug, cimetidine, was observed in the intestinal lumen from jejunal but not ileal perfusion in rats. The thioether amino acid, methionine, and the anion-exchange inhibitor, DIDS, were shown to inhibit metabolite appearance in rats. Appearance of cimetidine sulfoxide was also confirmed in jejunal perfusions in human subjects. Based on these preliminary findings, cimetidine will be used as a probe for 1) identifying intestinal flavin monooxygenase (FMO) isozymes as a function of intestinal region in rat and human; 2) examining mechanisms of intestinal secretion of drug and metabolite; 3) delineating the role of intestinal drug and metabolite clearance in contributing to variability in drug plasma level profiles. Cimetidine's special value as a probe for these oral drug delivery factors stems from 1) its capacity to inhibit cytochrome P450 providing for oxidation dominated by FMO; 2) its interactions with intestinal membrane transporters; 3) its pharmacokinetic properties which dictate a double peak in drug plasma level versus time plots, respectively. Species and regional differences in intestinal metabolism will be investigated in rat and human tissue homogenates as well as in rat in situ perfusion studies. Drug-drug and drug-nutrient interactions utilizing intestinal cimetidine sulfoxidation will be explored mechanistically in rat intestinal perfusions and investigated for pharmacokinetic impact in human perfusion studies. Drug oxidation-reduction kinetics will be detailed in intestinal subcellular fractions and directionality of drug and metabolite transport will be studied in intestinal tissue mounted in Ussing chambers. The potential for paracellular bypass to reduce the extent of intestinal clearance will be examined both in vitro and in situ. Contributions to variable clearance as a function of drug concentration and intestinal residence time will be studied in situ with the controlled input afforded in intestinal perfusion experiments. Studies to uncouple cellular metabolism from export kinetics will be performed with drug and metabolite-loaded membrane vesicles. The intestinal transport and metabolite data obtained in these studies will be coupled with other pharmacokinetic parameters in a physiologic model to project the impact of intestinal clearance on drug plasma levels. The model will be used to predict the influence of intestinal clearance on pharmacokinetics of new and existing drugs which show inhibition of cimetidine clearance in these in situ and in vitro systems of study. Intestinal metabolism/export of xenobiotics is an area of investigation that has received little attention. It is the goal of this research proposal to expand this knowledge base in animal and human studies. The tools developed in this study will be used to explore the intestinal metabolism of other drug classes. The biochemical mechanisms underlying these preliminary in situ observations may have more general implications for the GI tract as an organ of drug elimination.

拟议研究的长期目标是确定 肠清除率对药物血浆水平变异性影响。 在 初步研究，大量出现 在肠道中观察到硫醚咪唑药物西咪替丁， 肠腔从空肠灌注，而不是回肠灌注。 硫醚氨基 酸，蛋氨酸和阴离子交换抑制剂，DIDS，被证明是 抑制大鼠代谢产物出现。 西咪替丁亚砜的外观 在人类受试者的空肠灌注中也得到了证实。 基于这些初步的发现，西咪替丁将被用作探针 用于1）将肠黄素单加氧酶（FMO）同工酶鉴定为 大鼠和人类肠道区域功能; 2）检查 药物和代谢物的肠道分泌; 3）描绘的作用， 肠道药物和代谢物清除有助于 药物血浆水平曲线。 西咪替丁作为探针的特殊价值 这些口服药物递送因素源于1）其抑制 细胞色素P450提供由FMO主导的氧化; 2）其 与肠膜转运蛋白的相互作用; 3）其药代动力学 决定药物血浆水平与时间的双峰的性质 图，分别。 肠道代谢的物种和地区差异将 在大鼠和人体组织匀浆以及大鼠原位中研究 灌注研究。 药物-药物和药物-营养素相互作用 肠内西咪替丁磺基氧化将探讨机制， 大鼠肠灌注，并研究了对 人体灌注研究。 药物氧化还原动力学将是 详细描述了肠亚细胞组分和药物方向性 和代谢物转运将在安装在 尤辛·钱伯斯。 细胞旁旁路术减少 将在体外和原位检查肠清除的程度。 作为药物浓度函数的可变清除率贡献 和肠道停留时间将在原位进行研究， 肠灌注实验中提供的输入。 分离研究 来自输出动力学的细胞代谢将用药物进行， 负载代谢物的膜囊泡。 这些研究中获得的肠道转运和代谢物数据 将与生理学中的其他药代动力学参数相结合。 模型来预测肠清除对药物血浆水平的影响。 该模型将用于预测肠清除率对 显示出抑制的新药和现有药物的药代动力学 西咪替丁清除率在这些原位和体外系统的研究。 外源性物质的肠道代谢/输出是一个研究领域 很少受到关注。 这是本研究的目标 建议在动物和人类研究中扩大这一知识基础。 的 本研究中开发的工具将用于探索肠道 其他药物类别的代谢。 潜在的生化机制 这些初步的现场观测可能具有更普遍的意义 胃肠道是药物的排泄器官