MUCOSAL CELL CARRIERS ENZYMES IN ORAL DRUG ABSORPTION

拟议研究的长期目标是开发一种 改善多肽和多肽口服给药的机理基础 就像毒品一样。前一批款期的结果已确定(1) β-内酰胺类抗生素的肠道转运参数； 合成了α-甲基多巴的多肽前体药物，并表明它们具有 更高的肠膜通透性；(3)这些多肽 前药被粘膜细胞酶水解；以及(4)表明 评估口服药物吸收的理论框架是成功的 对于被动型和载体介导型化合物。此外，这部小说 发现血管紧张素转换酶抑制剂(卡托普利和依那普利)被 肽载体途径和卡托普利是粘膜的底物 细胞脯氨酸酶大大增加了对糖尿病的治疗意义。 这些研究。 建议的授权期的具体目标是：(1)延长 粘膜细胞转运参数的实验测定 更广泛的双肽和三肽类似物，以开发基础 这种膜运输系统的分子结构要求。 (2)建立基于传输参数和使用的结合部位模型 该模型指导进一步的结合部位模型的精化，化合物 选择和前药测试。(3)开发和推广前药方法 利用多肽载体转运改善口服给药 途径结合胞浆酶的研究作为 水解(再转化)部位。(四)扩大对口腔的调查 500~2000年间多肽的吸收和代谢 分子量范围。(5)发展和扩大肠道吸收 该模型将：(A)预测其化合物的吸收程度 吸收机制是载体介导的，如β-内酰胺类抗生素 和血管紧张素转换酶抑制剂：(B)考虑到非线性因素，如 溶解度/溶解极限，非线性(浓度相关) 膜通透性与管腔和刷缘代谢：(C) 考虑药物-药物和药物-营养(食物)的相互作用。 多肽结构要求的进一步发展 载体和延伸到更大的多肽，结合 可以估计人类口服给药的模型的开发将提供 为改善多肽的口服给药提供了基础。评选结果 拟议的研究将增加治疗的可能性 基于高活性多肽的多肽和多肽类药物的益处 内在活性，例如ACE抑制剂、肾素抑制剂、脑啡肽 类似物、促黄体生成素类似物、心房肽、生长激素等可以是 用来改善人类健康。

The long term objective of the proposed research is to develop a mechanistic basis for improving the oral delivery of peptide and peptide like drugs. The results of the previous grant period have (1) determined the intestinal transport parameters of the Beta-lactam antibiotics; (2) synthesized peptide prodrugs of alpha methyldopa and shown that they have much higher intestinal membrane permeabilities; (3) that these peptide prodrugs are hydrolyzed by mucosal cell enzymes; and (4) shown that a theoretical framework for estimating oral drug absorption is successful for both passive and carrier mediated compounds. In addition, the novel finding that ACE inhibitors (captopril and enalapril) are absorbed by the peptide carrier pathway and that captopril is a substrate for the mucosal cell prolidase enzyme greatly increases the therapeutic significance of these studies. The specific aims for the proposed grant period are: (1) Extend the experimental determination of mucosal cell transport parameters to a wider range of di- and tripeptide analogs in order to develop a basis for the molecular structural requirements for this membrane transport system. (2) Develop binding site models based on the transport parameters and use the models to guide further binding site model refinement, compound selection and prodrug testing. (3) Develop and extend a prodrug approach to improving oral drug delivery using the peptide carrier transport pathway combined with the investigation of cytosolic enzymes as the hydrolysis (reconversion) sites. (4) Extend the investigation of oral peptide absorption and metabolism to peptides in the 500 to 2000 molecular weight range. (5) Develop and extend an intestinal absorption model that will: (a) predict the extent of absorption of compounds whose absorption mechanism is carrier mediated, e.g., Beta-lactam antibiotics and ACE inhibitors: (b) account for nonlinear factors such as solubility/dissolution limits, nonlinear (concentration dependent) membrane permeability and luminal and brush-border metabolism: (c) account for drug-drug and drug-nutrient (food) interactions. The further development of the structural requirements for the peptide carrier and the extension to larger peptides, combined with the development of models that can estimate human oral delivery will provide a basis for improving the oral delivery of peptides. The results of the proposed research will increase the likelihood that the therapeutic benefits of peptide and peptide-like drugs based on peptides of high intrinsic activity, e.g., ACE inhibitors, renin inhibitors, enkephalin analogs, LH-RH analogs, atrial peptides, growth hormones, etc., can be used to improve human health.