ABSORPTION OF RETINOIDS FROM THE GASTROINTESTINAL TRACT

胃肠道对类维生素A的吸收

• 批准号: 2096650
• 负责人: CHERYL L ZIMMERMAN
• 金额: $ 12.31万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096650
• 关键词: 13 cis retinoate; artificial membranes; brush border membrane; chemical structure function; cholanate compound; conformation; gastrointestinal drug absorption; laboratory rat; lipid transport; membrane model; micelles; perfusion; phospholipids; retinoate; retinoids; stereochemistry; water solubility

The retinoids are analogues of Vitamin A and have earned a prominent role in the treatment of dermatological disorders. However, the extent of their true potential may yet be realized in cancer chemoprevention and treatment. Consequently, structure-activity relationships have been studied in an attempt to uncouple the structural features which are responsible for pharmacological activity from those causing toxicity to the host. However, the in vivo activity of a given retinoid is not necessarily well-predicted by its in vitro pharmacological activity. The oral absorption is of particular concern since the structural modifications which enhanced pharmacological activity would be expected to lead to a decrease in aqueous solubility with a resultant decrease in bioavailability. However, bile salt micelle solubilization and transport is known to be important for the absorption of retinol. If better understood, this process could be exploited to achieve the oral delivery of insoluble drugs with high intrinsic pharmacological activity. The specific aims of this project are to study the influence of chemical structure on the initial steps in retinoid absorption by the intestine: solubilization of the retinoid by bile salt mixed micelles, transport through the aqueous boundary layer, and transfer of the retinoid from the mixed micelle to the brush border membrane of the enterocyte. To evaluate the influence of chemical structure on absorption of retinoids, two classes of retinoic acid analogues will be evaluated. The first class of molecules are all-trans-retinoic acid analogues with various functional groups in the hydrophilic portion of the molecule. These analogues will include: all-trans-retinoic acid, 13-cis-retinoic acid (isotretinoin), all-trans-retinoic acid ethyl ester, N- ethylretinamide, retinyl methyl ether, and N-(4-hydroxyphenyl)retinamide. The second class of retinoic acid analogues will contain sterically restricted conformations in the polyene chain. The structural rigidity of these compounds, known as arotinoids, would be hypothesized to influence the extent of solubilization in the mixed micelles that mediate the absorption of the retinoids from the intestinal lumen. To understand the structural requirements that determine the extent of absorption, the following specific studies will be carried out. the retinoid physicochemical properties relevant to intestinal absorption, including aqueous solubility, bulk phase partition coefficient, bile acid mixed micelle/aqueous distribution coefficient and the bile acid mixed micelle/phospholipid membrane vesicle transfer rate and distribution coefficient will be evaluated. These physicochemical properties will then be related to the absorption of the retinoids as determined in the in situ perfused rat intestinal lumen model. The ultimate goal of the work is the establishment of chemical design features which will maximize the oral bioavailability of the retinoids by improvement of absorption from the gastrointestinal lumen.

类维生素类似是维生素A的类似物，并且赢得了重要的作用 在治疗皮肤病。 但是， 在癌症化学预防和 治疗。 因此，结构活动关系已经 研究以揭开结构特征的尝试 负责导致毒性的药理学活性 主人。 但是，给定类维生素类似的体内活性不是 必须通过其体外药理活性得到很好的预测。 这 口服吸收特别关注 预计会增强药理活性的修改 导致水溶性降低，导致结果降低 生物利用度。 但是，胆汁盐胶束溶解和运输 已知对于视黄醇的吸收很重要。 如果更好 理解，可以利用此过程来实现口头交付 具有较高内在药理活性的不溶性药物。 该项目的具体目的是研究化学的影响 结构在肠道吸收的视黄吸收的初始步骤上： 通过胆汁盐混合胶束溶解性类维生素，转运 穿过水边界层，从 将胶束混合到肠肠细胞的刷子边界膜。 评估化学结构对吸收的影响 视力素，将评估两类视黄酸类似物。 这 一流的分子是全反毒酸类似物 分子的亲水部分中的各种官能团。 这些类似物将包括：全反替酸，13 cis-反替酸 酸（异维使用诺），全反击毒酸乙酯，n- 乙酰胺，视乙酰甲基醚和N-（4-羟基苯基）视网膜酰胺。 第二类视黄酸类似物将包含在空间上 多元链中的构象受限。 结构刚度 在这些化合物中，称为原子素，将假设 影响介导的混合胶束中的溶解化程度 从肠腔吸收性类视网膜生物的吸收。 了解确定程度的结构要求 吸收，将进行以下具体研究。 这 类维生素性的物理化学特性与肠吸收有关， 包括水溶性，大相分区系数，胆汁酸 混合胶束/水分布系数和胆汁酸混合 胶束/磷脂膜囊泡转移速率和分布 系数将进行评估。 这些理化特性将 然后与在确定的类维生素类动物的吸收有关 原位灌注大鼠肠腔模型。 最终目标 工作是建立化学设计功能，它将最大化 类维生素的口服生物利用度通过改善吸收 从胃肠道腔。