抄録
Various approaches have been examined to improve peptide and peotein drugs via gastrointestinal tract. In a series of investigation, we have synthesized noveI lipophilic derivatives of thyrotropin-releasing hormone, tetragastrin, and insulin by chemical modification with different carbon-chain length fatty acids. In this study, we synthesized newly lipophilic derivatives of human calcitonin(hCT) by chemical modification with short-chain length fatty acids, such as acetic acid (C2) and caproic acid (C6), and examined their intestinal absorption properties using an in situ closed loop method in rats and their stabilities in the intestinal mucosal homogenates. The intestinal absorption properties of acyl derivatives were estimated by calculating the pharmacological availability (PA). Their intestinal absorption and stability in the intestinal mucosal homogenates were improved by acylation in the following rank order : caproylated hCT>acetylated hCT>native hCT. Furthermore, we studied the effects of co-administered absorption enhancer, sodium glycocholate (Na-GC), on the intestinal absorption of acyl-hCT derivatives. Co-administration of Na-GC significantly improved the absorption of native hCT from the intestine. However, the promoting effect of Na-GC was found to be less pronounced for the acyl derivatives, although Na-GC enhanced their absorption by about twice. These results indicated that it may be possible to achieve remarkable absorption enhancement by hCT by using a combination of acylation and Na-GC.
