Yamamoto A, Okagawa T, Kotani A, Uchiyama T, Shimura T, Tabata S, Kondo S, Muranishi S
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
J Pharm Pharmacol. 1997 Nov;49(11):1057-61. doi: 10.1111/j.2042-7158.1997.tb06041.x.
The permeation of ebiratide (H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2), a novel ACTH analogue, across the intestinal mucosae has been examined by use of isolated intestinal membranes from rats in a modified Ussing chamber. Regional differences were observed in the permeation of ebiratide across intestinal membranes; the order of membrane permeability was jejunum > ileum > duodenum > colon. Overall, the permeation of ebiratide was relatively poor. The effects of various absorption enhancers were examined to increase the intestinal permeability to ebiratide. Sodium glycocholate and sodium caprate had no significant enhancing effect on the permeability of the jejunal membrane, but significantly enhanced the permeation of ebiratide through the colonic membrane. On the other hand, N-dodecyl-beta-D-maltopyramoside (LM) significantly enhanced the permeation of ebiratide through both jejunal and colonic membranes. In general, the absorption-enhancing effects of these agents were more predominant in the colon than in the jejunum. Membrane damage by the absorption enhancers was evaluated by measuring the amount of protein released from the intestinal membrane. It was found that all the absorption enhancers slightly increased the amount of protein released, but that the amounts of protein released in the presence of these enhancers were much less than in the presence of ethylenediaminetetraacetic acid (EDTA), used as a positive control. These findings suggest that the absorption enhancers, especially LM might be useful adjuvants for improving the intestinal absorption of peptide and protein drugs, including ebiratide.
新型促肾上腺皮质激素类似物艾替瑞肽（H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2）通过改良的Ussing室中大鼠的离体肠膜来检测其对肠黏膜的渗透情况。观察到艾替瑞肽在肠膜渗透中的区域差异；膜通透性顺序为空肠＞回肠＞十二指肠＞结肠。总体而言，艾替瑞肽的渗透相对较差。研究了各种吸收促进剂对提高艾替瑞肽肠通透性的影响。甘氨胆酸钠和癸酸钠对空肠膜通透性无显著增强作用，但显著增强了艾替瑞肽通过结肠膜的渗透。另一方面，N-十二烷基-β-D-麦芽糖苷（LM）显著增强了艾替瑞肽通过空肠和结肠膜的渗透。一般来说，这些药物的吸收增强作用在结肠中比在空肠中更显著。通过测量从肠膜释放的蛋白量来评估吸收促进剂对膜的损伤。发现所有吸收促进剂均轻微增加了蛋白释放量，但在这些促进剂存在下释放的蛋白量远低于用作阳性对照的乙二胺四乙酸（EDTA）存在时的释放量。这些发现表明，吸收促进剂，尤其是LM可能是改善包括艾替瑞肽在内的肽类和蛋白质药物肠道吸收的有用佐剂。
