Yodoya E, Uemura K, Tenma T, Fujita T, Murakami M, Yamamoto A, Muranishi S
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
J Pharmacol Exp Ther. 1994 Dec;271(3):1509-13.
Three types of chemically modified tetragastrin (TG) with fatty acids such as acetyl-TG, caproyl-TG and lauroyl-TG were synthesized and their in vitro intestinal permeability characteristics were estimated by a modified Ussing chamber system using the isolated intestinal membrane of rats. The penetration of TG across the large intestine was increased by conjugation with acetic acid and caproic acid but not lauric acid. Lauroyl-TG, a highly lipophilic derivative, exhibited low permeability across the intestinal membrane. A "bell-shaped" profile was observed between the apparent permeability coefficients and lipophilicity of the acyl-TG derivatives. The stability of acyl-TG derivatives was examined in homogenates of the jejunum, proximal and distal large intestine, liver and plasma. The half-lives for the proteolysis of the TGs were significantly prolonged by chemical modification with fatty acids in each homogenate. Thus, the chemical modification of TG with some fatty acids not only increases the lipophilicity of TG but also reduces its degradation, which resulted in increased intestinal absorption. The extent of the conjugates' hepatic first-pass metabolism was evaluated by gastric acid secretion activities after i.v. and intraportal administration. The amount of gastric acid secretion after intraportal administration of TG was significantly reduced in comparison with that after i.v. administration. On the other hand, conjugation with caproic acid slightly suppressed TG's hepatic first-pass metabolism, which suggests that chemically modified TGs with fatty acids would be more stable than the native TG in the systemic circulation after intestinal absorption.
合成了三种用脂肪酸化学修饰的四肽胃泌素（TG），即乙酰化-TG、己酰化-TG和月桂酰化-TG，并使用大鼠离体肠膜，通过改良的尤斯灌流小室系统评估了它们的体外肠道通透性特征。与乙酸和己酸结合可增加TG在大肠中的渗透，但与月桂酸结合则不然。月桂酰化-TG是一种高度亲脂性衍生物，在肠膜上的通透性较低。在酰基-TG衍生物的表观渗透系数和亲脂性之间观察到一种“钟形”曲线。在空肠、近端和远端大肠、肝脏和血浆的匀浆中检测了酰基-TG衍生物的稳定性。在每种匀浆中，通过脂肪酸化学修饰显著延长了TG蛋白水解的半衰期。因此，用某些脂肪酸对TG进行化学修饰不仅增加了TG的亲脂性，还减少了其降解，从而导致肠道吸收增加。通过静脉注射和门静脉注射后的胃酸分泌活性评估了缀合物肝首过代谢的程度。与静脉注射后相比，门静脉注射TG后胃酸分泌量显著减少。另一方面，与己酸结合略微抑制了TG的肝首过代谢，这表明用脂肪酸化学修饰的TG在肠道吸收后的体循环中比天然TG更稳定。
