DRUG TRANSPORT IN THE GI TRACT AND OTHER EPITHELIA

这一建议旨在阐明核糖核酸的运输机制。 药理活性的弱电解质穿过衬里的上皮细胞 胃肠道。建议目前被接受的模式是 这些运输过程(pH分配假说)过于简单化 机构的表示，以及更复杂的三室系统 需要充分描述运输过程的特点。 该方案包括三种类型的实验：(1)体内研究 药物的吸收和分泌将允许检查 三室模型作为一种适用范围广、且完全定量的模型 药物转运机制的描述。(2)人工合成药物的体外研究 膜和上皮细胞将被用来鉴定和评估 弱电解质渗透的决定因素。(3)生物物理、生物化学 将使用方法来表征负责以下任务的过程 作为驱动力的上皮内pH梯度的建立 用于弱电解质跨上皮细胞的净转运。 该项目将专注于开发生理学和药理学 管制药物运输的方法，以及药物管制机构的作用 作为药物相互作用部位的消化上皮细胞。我们将特别注意 重视消化上皮细胞在药物动力学中的意义 常见的滥用药物，包括巴比妥酸盐、麻醉剂和麻醉剂 拮抗剂，以及改变食物的可能性 运输过程可能有助于从中毒中恢复过来 物质。

This proposal is directed to the elucidation of mechanisms for transport of pharmacologically active weak electrolytes across the epithelia lining the gastro-intestinal tract. It is suggested that the currently accepted model for these transport processes (the pH partition hypothesis) is an overly simplistic representation of mechanism, and that a more complex, three compartment system is required to fully delineate the characteristics of the transport processes. The proposal includes three types of experiments (1) In vivo studies on the absorption, and secretion of drugs will allow examination of the utility of the three compartment model as a broadly applicable, and fully quantitative description of drug transport mechanisms. (2) In vitro studies on synthetic membranes, and on epithelia will be used to identify, and evaluate the determinants of weak electrolyte permeation. (3) Biophysical, and biochemical approaches will be used to characterize the processes responsible for the establishment of the intra-epithelial pH gradients which are the driving forces for net transport of weak electrolytes across epithelia. The project will focus on the development of physiological, and pharmacological approaches to the regulation of drug transport, and on the roles of the alimentary epithelia as loci of drug interactions. Particular attention will be paid to the significance of the alimentary epithelia in the pharmacokinetics of common drugs of abuse, including the barbiturates, narcotics, and the narcotic antagonists, and to the possibility that modification of the alimentary transport processes may facilitate recovery from intoxication with these substances.