Yamamoto A
Department of Biopharmaceutics, Kyoto Pharmaceutical University.
Nihon Rinsho. 1998 Mar;56(3):601-7.
It is well known that the oral bioavailability of peptide and protein drugs is generally poor because they are extensively degraded by proteases in the gastrointestinal tract and impermeable through the intestinal mucosa. Therefore, various approaches have been examined to overcome the delivery problems of these peptides and to improve their absorption via the gastrointestinal tract. Of these approaches, a potentially useful approach to solve these delivery problems may be chemical modification of peptides and proteins to produce prodrugs and analogues. Thus, it is plausible that this approach may protect peptides against degradation by peptidases and other enzymes present at the mucosal barrier and renders the peptides and proteins more lipophilic, resulting in increased bioavailability. From these standpoints, we synthesized lipophilic derivatives of peptides and proteins such as thyrotropin-releasing hormone (TRH), tetragastrin (TG), calcitonin and insulin by chemical modification with fatty acids. The pharmacological activities of these derivatives were relatively high as compared with the native peptides. A significant increase in the intestinal absorption of these derivatives of peptides was observed in comparison with native peptides. Overall, the effects of acylation on the intestinal absorption of these peptides were more predominant in the large intestine than those in the small intestine. In addition, these derivatives were more stable than the parent peptides in homogenates of the various intestinal mucosae. We also examined the intestinal transport characteristics of TG and its acyl derivatives using Caco-2 cell monolayers in order to assess the contribution of enzymatic and transport barriers on their intestinal absorption. The degradation clearance of TG on the apical membrane was decreased by chemical modification with fatty acids. In addition, the permeability clearance of TG was improved by the acylation. On the other hand, the intestinal absorption of thyrotropin releasing hormone (TRH), which is transported by a carrier-mediated process, was also enhanced by chemical modification with lauric acid. In summary, this chemical modification approach may be useful to improve the intestinal absorption of peptide and protein drugs.
众所周知，肽类和蛋白质药物的口服生物利用度通常较差，因为它们在胃肠道中会被蛋白酶广泛降解，且无法透过肠黏膜。因此，人们已经研究了各种方法来克服这些肽类药物的递送问题，并改善它们通过胃肠道的吸收。在这些方法中，一种可能有用的解决这些递送问题的方法可能是对肽和蛋白质进行化学修饰以产生前药和类似物。因此，这种方法可能会保护肽不被存在于黏膜屏障处的肽酶和其他酶降解，并使肽和蛋白质更具亲脂性，从而提高生物利用度，这似乎是合理的。从这些角度出发，我们通过用脂肪酸进行化学修饰，合成了肽和蛋白质的亲脂性衍生物，如促甲状腺激素释放激素（TRH）、四肽胃泌素（TG）、降钙素和胰岛素。与天然肽相比，这些衍生物的药理活性相对较高。与天然肽相比，观察到这些肽衍生物的肠道吸收有显著增加。总体而言，酰化对这些肽肠道吸收的影响在大肠中比在小肠中更显著。此外，这些衍生物在各种肠黏膜匀浆中比母体肽更稳定。我们还使用Caco-2细胞单层研究了TG及其酰基衍生物的肠道转运特性，以评估酶促和转运屏障对它们肠道吸收的影响。脂肪酸化学修饰降低了TG在顶端膜上的降解清除率。此外，酰化提高了TG的通透清除率。另一方面，通过月桂酸化学修饰也增强了通过载体介导过程转运的促甲状腺激素释放激素（TRH）的肠道吸收。总之，这种化学修饰方法可能有助于改善肽类和蛋白质药物的肠道吸收。
