MUCOSAL CELL CARRIERS ENZYMES IN ORAL DRUG ABSORPTION

口腔药物吸收中的粘膜细胞载体酶

• 批准号: 3292313
• 负责人: GORDON L AMIDON
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3292313
• 关键词: aminoacid; aminopeptidase; beta lactam antibiotic; cephalosporins; dogs; drug administration routes; drug design /synthesis /production; drug vehicle; enzyme mechanism; gastrointestinal drug absorption; high performance liquid chromatography; hydrolysis; laboratory rat; mathematical model; membrane permeability; pancreas enzyme; penicillins; peptidases; peptide analog; pharmacokinetics; prodrugs; proteolysis; transport proteins

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.

拟议研究的长期目标是开发 改善肽和肽口服递送的机械基础 喜欢药物。上一个赠款期的结果已确定（1） β-内酰胺抗生素的肠运输参数； （2） 合成α甲基多达的肽前药，并表明它们具有 更高的肠膜渗透率； （3）这些肽 前药被粘膜细胞酶水解； （4）表明 估计口服药物吸收的理论框架成功 用于被动和载体介导的化合物。此外，小说 发现ACE抑制剂（Captopril和Enalapril）被 肽载体途径，而卡托普利是粘膜的底物 细胞脯氨酸酶大大提高了治疗意义 这些研究。 提议的赠款期的具体目的是：（1）扩展 实验确定粘膜细胞转运参数到A 更广泛的二肽和三肽类似物，以建立一个基础 该膜传输系统的分子结构要求。 （2）根据传输参数开发绑定站点模型并使用 指导进一步结合位点模型改进的模型，化合物 选择和前药测试。 （3）开发和扩展一种前药方法 使用肽载体运输改善口服药物输送 途径与胞质酶的研究合并为 水解（调节）位点。 （4）扩展口服调查 500至2000年肽的肽吸收和代谢 分子量范围。 （5）发展和扩展肠吸收 将：（a）预测化合物吸收程度的模型 吸收机制是载体介导的，例如β-内酰胺抗生素 和ACE抑制剂：（b）考虑到非线性因素，例如 溶解度/溶解极限，非线性（浓度依赖） 膜的渗透性以及腔和刷子代谢：（c） 考虑药物 - 药物和药物（食品）相互作用。 肽结构要求的进一步发展 载体和较大肽的延伸，结合 开发可以估计人口腔交付的模型将提供 改善口服肽的基础。结果 拟议的研究将增加治疗性的可能性 基于高肽的肽和肽样药物的益处 固有活性，例如ACE抑制剂，肾素抑制剂，Enkephalin 类似物，LH-RH类似物，心房肽，生长激素等可以是 用于改善人类健康。