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INTESTINAL ABSORPTION/METABOLISM OF H2 ANTAGONISTS

H2 拮抗剂的肠道吸收/代谢

基本信息

批准号：
2189038
负责人：
DAVID FLEISHER
金额：
$ 10万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-01 至 1996-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2189038
关键词：
antihistamines drug metabolism gastrointestinal drug absorption

项目摘要

This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. The long-term objective of the proposed research is to determine the influence of intestinal metabolism on the oral availability of histamine- receptor2 (H2) antagonists. In preliminary studies, substantial appearance of the sulfoxide metabolite was observed in the intestinal lumen from jejunal but not ileal perfusion of cimetidine in rats. Furthermore appearance of metabolite in rat jejunum was blocked by a mucosal anion exchange inhibitor. Cimetidine sulfoxide was also observed in two human jejunal perfusions but to a lesser extent than in rats. The four commercially-available H2-antagonists (cimetidine, ranitidine, famotidine and nizatidine) are among the most frequently prescribed legend drugs. Their oral bioavailabilities differ significantly but double plasma level peaks are characteristic of all four drugs. Hepatic sulfoxidation profiles also differ and it has been postulated that diminished clearance of sulfoxide metabolites contribute to the central nervous system toxicity of this class of agents. Intestinal metabolism and metabolite export may constitute a significant mode of elimination for the H2-antagonists that has not been previously uncovered. The site- specific nature of intestinal clearance may account for double-peaking and metabolic differences may account for bioavailability differences. Drug and species differences in intestinal metabolism will be investigated in rat and human perfusion studies. Intestinal reduction of sulfoxide metabolite, possible systemic clearance via the intestine and fed-state effects on intestinal clearance will be studied in rat perfusions. Metabolism kinetics will be studied in intestinal cell suspensions and kinetics and directionality of drug and metabolite transport will be investigated in Ussing chambers using both intestinal tissue and Caco-2 cell monolayers. Studies to uncouple cellular metabolism from metabolite export kinetics will be performed with cimetidine sulfoxide-loaded brush border membrane vesicles. Drug intestinal permeability and metabolite data obtained from human perfusion studies will be incorporated in a physiologic model utilizing existing information on renal and hepatic clearance to project the impact of intestinal metabolism and absorption variability on drug and metabolite plasma levels. Mechanistic details from the more isolated studies will be utilized to refine model parameters obtained from perfusions. 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 with a group of agents enjoying extensive clinical utility. If H2-antagonist intestinal metabolism and/or export prove to have a significant impact on drug plasma level variability, 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.

这是香农奖，为研究提供部分支持未达到指定机构资助范围但处于卓越的边缘。香农奖旨在提供支持以测试该方法的可行性；进一步发展测试和完善研究技术；进行二次分析可用的数据集；或进行可以证明的离散项目 PI 的研究能力或对已经存在的研究给予额外的重视有功的应用。以下摘要摘自原文主要研究者提交的文件。拟议研究的长期目标是确定肠道代谢对组胺口服利用率的影响受体 2 (H2) 拮抗剂。在初步研究中，大量在肠道中观察到亚砜代谢物的出现在大鼠中从空肠而不是回肠管腔灌注西咪替丁。此外，大鼠空肠中代谢物的出现被粘膜阴离子交换抑制剂。还观察到西咪替丁亚砜在两次人类空肠灌注中，但程度低于大鼠。四种市售 H2 拮抗剂（西咪替丁、雷尼替丁、法莫替丁和尼扎替丁）是最常用的处方药物之一传奇药物。它们的口服生物利用度差异很大，但双血浆水平峰是所有四种药物的特征。肝的磺化氧化特征也不同，并且推测亚砜代谢物的清除减少有助于中枢此类药剂有神经系统毒性。肠道代谢代谢物输出可能构成一种重要的消除方式对于之前尚未发现的 H2 拮抗剂。该网站- 肠道清除的特殊性质可能是双峰的原因代谢差异可能导致生物利用度差异。肠道代谢的药物和物种差异将在大鼠和人体灌注研究中进行了研究。肠道缩小亚砜代谢物，可能通过肠道全身清除将在大鼠中研究进食状态对肠道清除率的影响灌注。将研究肠细胞的代谢动力学药物和代谢物的悬浮液、动力学和方向性将在使用室中使用肠道来研究运输组织和 Caco-2 细胞单层。细胞解偶联研究代谢物输出动力学的代谢将通过负载西咪替丁亚砜的刷状缘膜囊泡。从人体获得的药物肠道通透性和代谢数据灌注研究将被纳入生理模型中，利用关于肾脏和肝脏清除率的现有信息以预测影响药物的肠道代谢和吸收变异性血浆代谢水平。来自更孤立的机械细节研究将用于完善从以下获得的模型参数灌注。肠道代谢/异生物质的输出是一个研究领域这很少受到关注。这是本研究的目标建议扩大动物和人类研究的知识库一组具有广泛临床用途的药物。如果H2-拮抗剂肠道代谢和/或输出被证明具有重大影响关于药物血浆水平的变异性，本研究开发的工具将可用于探索其他药物类别的肠道代谢。这这些初步现场观察背后的生化机制可能对胃肠道作为药物器官有更普遍的影响消除。