ABSORPTION CHARACTERISTICS OF CHEMICALLY MODIFIED-INSULIN DERIVATIVES WITH VARIOUS FATTY-ACIDS IN THE SMALL AND LARGE-INTESTINE
ABSORPTION CHARACTERISTICS OF CHEMICALLY MODIFIED-INSULIN DERIVATIVES WITH VARIOUS FATTY-ACIDS IN THE SMALL AND LARGE-INTESTINE
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DOI：
10.1002/jps.2600840604
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发表时间：
1995-06-01
影响因子：
3.8
通讯作者：
MURANISHI, S
中科院分区：
文献类型：
--
作者：
ASADA, H;DOUEN, T;MURANISHI, S
用原位环法和体外改良Ussing小室法测定了不同脂肪酸化学修饰的胰岛素衍生物在肠道中的吸收特性。根据静脉给药后的降血糖效果，这些酰基衍生物的药理活性随着与天然胰岛素化学结合的脂肪酸(S)碳数的增加而降低。然而，当单丙基和二丙基衍生物静脉给药时，发现有很高的药理活性。胰岛素在小肠给药后的吸收很难通过酰化作用得到改善。相反，在大肠给药后，通过增加附着在胰岛素上的己酸分子的数量来增加其吸收。此外，通过体外改进的Ussing小室方法，发现胰岛素对十二指肠和结肠粘膜的通透性也随着己酸分子数量的增加而提高。上述体内和体外实验结果表明，用脂肪酸对胰岛素进行化学修饰是提高胰岛素在大肠吸收的有效途径。
Absorption characteristics of insulin derivatives chemically modified with various fatty acids in the intestine were determined by in situ loop and in vitro modified Ussing chamber methods. The pharmacological activities of these acyl derivatives, as assessed by their hypoglycemic effects after intravenous administration, were reduced upon increasing the carbon number of the fatty acid(s) chemically attached to native insulin. However, high pharmacological activities were seen when mono- and dicaproyl derivatives were administered intravenously. The absorption of insulin after its small intestinal administration could be hardly improved by acylation. In contrast, its absorption after the large intestinal administration was increased by increasing the number of caproic acid molecules attached to insulin. Furthermore, by an in vitro modified Ussing chamber method, it was revealed that the permeability of insulin across both the duodenal and colonic mucous membranes was also improved by increasing the number of caproic acid molecules. These in situ and in vitro results indicated that the chemical modification of insulin with fatty acids was a useful approach for improving insulin absorption from the large intestine.