INTESTINAL ABSORPTION/METABOLISM OF H2 ANTAGONISTS

这是香农奖，为这项研究提供部分支持 项目低于指定研究所的资助范围，但 都处于最优秀的边缘。香农奖旨在 为测试该方法的可行性提供支持；进一步发展 测试和改进研究技术；执行二次分析 可用的数据集；或执行可演示的离散项目 PI的研究能力或为已经 值得称道的申请。以下摘要摘自原文 首席调查员提交的文件。 拟议研究的长期目标是确定 肠道代谢对组胺口服利用度的影响 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。 大鼠空肠而不是回肠灌流西咪替丁。 此外，大鼠空肠中代谢物的出现被一种 粘膜阴离子交换抑制剂。西咪替丁亚砜也观察到 在两次人类空肠灌流中，但程度低于大鼠。 四种商用的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 传奇药物。它们的口服生物利用度差异很大，但 所有四种药物的特征都是双峰血浆水平。肝脏 亚磺化作用的剖面也不同，据推测 亚砜代谢物的清除减少对中枢 这类制剂的神经系统毒性。肠道代谢 代谢物输出可能构成一种重要的消除方式 对于H2-拮抗剂，这是以前没有发现的。该网站- 肠道清除的特殊性质可能是双峰型的原因 代谢差异可能是生物利用度差异的原因。 药物和物种在肠道代谢方面的差异将是 在大鼠和人的灌流研究中进行了研究。肠道复位术 亚砜代谢物，可能通过肠道进行全身清除 并将研究喂食状态对大鼠肠道清除的影响 输液。将研究肠道细胞的代谢动力学 药物和代谢物的混悬液及其动力学和方向性 将在Ussing小室中使用两种肠道进行传输研究 组织和Caco-2细胞单层。拆分细胞的研究 代谢物输出动力学中的代谢将通过 载西咪替丁亚砜的刷状缘膜囊泡。 人体药物肠道通透性和代谢物数据 血流灌注研究将被纳入一个生理模型，利用 关于肾脏和肝脏清除的现有信息，以预测影响 药物和药物的肠道代谢和吸收变异性 代谢物血浆水平。机械细节来自于更孤立的 将利用研究来改进从 输液。 异源物质的肠道代谢/出口是一个研究领域 这一点几乎没有受到关注。这就是本研究的目的。 在动物和人类研究中扩展这一知识库的建议 一组具有广泛临床用途的药物。如果是H2-拮抗剂 肠道新陈代谢和/或出口被证明具有重大影响 关于药物血浆水平的变异性，本研究中开发的工具将 可用于探索其他药物类别的肠道代谢。这个 这些初步原位观察背后的生化机制 可能对作为药物器官的胃肠道有更广泛的影响 淘汰赛。

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.