Yamamoto A, Hayakawa E, Kato Y, Nishiura A, Lee V H
University of Southern California, School of Pharmacy, Department of Pharmaceutical Sciences, Los Angeles.
J Pharmacol Exp Ther. 1992 Oct;263(1):25-31.
This study was conducted mainly to investigate the relative contributions of various mechanisms by which bile salts and EDTA may improve the in vitro rectal penetration of insulin in the albino rabbit. Insulin could not cross the rectal mucosa unless Na glycocholate or other penetration enhancers were present. Penetration enhancement was attributed primarily to Na glycocholate's ability to reduce the barrier function of the rectal membrane and to increase the fraction of insulin in its monomeric form, and secondarily to Na glycocholate's ability to protect insulin from proteolysis. Na glycocholate was more effective than Na taurocholate, but less effective than Na deoxycholate and polyoxyethylene-9-lauryl ether in enhancing rectal insulin penetration. Although EDTA at 0.01 and 0.1% did not affect rectal insulin penetration, it augmented the penetration enhancement effect of 1% Na glycocholate without causing additional damage to the rectal membrane, as judged by protein release. Such an action was attributed to the synergistic effect associated with: 1) an increase in the permeability of the paracellular pathway by EDTA and 2) an increase in the proportion of insulin in the monomeric form by Na glycocholate. Results from parallel in vivo experiments have indicated that it may be possible to achieve significant penetration enhancement by using a combination of otherwise membrane-damaging penetration enhancers which act by complementary mechanisms at concentrations that are both effective and well tolerated by mucosal epithelial cells.
本研究主要旨在探讨胆盐和乙二胺四乙酸（EDTA）改善胰岛素在白化兔体内直肠渗透的各种机制的相对作用。除非存在甘氨胆酸钠或其他渗透促进剂，胰岛素无法穿过直肠黏膜。渗透增强主要归因于甘氨胆酸钠降低直肠膜屏障功能以及增加胰岛素单体形式比例的能力，其次归因于甘氨胆酸钠保护胰岛素免受蛋白水解的能力。在增强直肠胰岛素渗透方面，甘氨胆酸钠比牛磺胆酸钠更有效，但比脱氧胆酸钠和聚氧乙烯-9-月桂醚效果差。尽管0.01%和0.1%的EDTA不影响直肠胰岛素渗透，但根据蛋白质释放判断，它增强了1%甘氨胆酸钠的渗透增强效果，且未对直肠膜造成额外损伤。这种作用归因于以下协同效应：1）EDTA增加细胞旁途径的通透性；2）甘氨胆酸钠增加胰岛素单体形式的比例。平行的体内实验结果表明，通过联合使用原本具有膜损伤作用的渗透促进剂，这些促进剂通过互补机制在对黏膜上皮细胞有效且耐受性良好的浓度下起作用，可能实现显著的渗透增强。
