INTESTINAL CLEARANCE--MECHANISMS & PLASMA LEVEL EFFECTS

拟议研究的长期目标是确定 肠道清除对药物血药浓度变异性的影响。在……里面 亚麻黄代谢产物的初步研究 一种硫代醚咪唑类药物西咪替丁在肠道中被观察到。 大鼠的肠腔来自空肠，而不是回肠灌流。硫醚氨基 酸、蛋氨酸和阴离子交换抑制剂DIDS被证明是 抑制大鼠体内代谢物的出现。西咪替丁亚砜的外观 在受试者的空肠灌流中也证实了这种情况。 根据这些初步发现，西咪替丁将被用作探针 1)将肠道黄素单加氧酶(FMO)同工酶鉴定为 大鼠和人的肠区功能；2)探讨其作用机制 肠道分泌的药物和代谢物；3)勾画作用 肠道药物和代谢物清除在导致变异性中的作用 药物血药浓度分布。西咪替丁作为探测药物的特殊价值 这些口服给药因子源于1)其抑制能力 细胞色素P450提供以FMO为主的氧化；2)其 与肠膜转运体的相互作用；3)药代动力学 药物血药浓度随时间呈双峰变化的特性 分别是情节。 肠道代谢的物种和地区差异将是 在大鼠和人组织匀浆中以及在大鼠体内的研究 血流灌注研究。利用药物-药物和药物-营养相互作用 肠道西咪替丁亚硫氧化将在#年进行机械探索 大鼠肠道灌流及其对药代动力学的影响 人体血流灌注研究。药物氧化还原动力学将是 详细介绍了肠道亚细胞成分和药物的方向性 并将研究代谢物在肠道组织中的运输 使用密室。细胞旁路转流的潜力可以减少 将在体外和在体上检查肠道清除的程度。 作为药物浓度函数的变量清除量的贡献 并与对照组进行肠道滞留时间的现场研究 在肠道灌流实验中提供的输入。研究要脱钩 来自出口动力学的细胞新陈代谢将通过药物和 代谢物负载的膜小泡。 在这些研究中获得的肠道转运和代谢物数据 会与其他药代动力学参数结合在一起 模型以预测肠道清除对血药浓度的影响。 该模型将被用来预测肠道清除对 显示抑制作用的新药和现有药物的药代动力学 西咪替丁在这些体内和体外系统中的清除性研究。 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。 建议在动物和人类研究中扩大这一知识库。这个 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 这些初步的现场观察可能具有更广泛的意义 作为排毒器官的胃肠道。

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.