Abstract
In order to improve the intestinal absorption of tetragastrin (TG), we synthesized lipophilic derivatives of TG by acylation of its N-terminal amino group with acetic acid, caproic acid, and lauric acid. The purified TG derivatives, acetyl-tetragastrin (Ac-TG), caproyl-tetragastrin (Cap-TG), and lauroyl-tetragastrin (Lau-TG), were confirmed to be more lipophilic than the parent TG by high-performance liquid chromatography (HPLC). The pharmacological activities and the intestinal absorption of TG and its derivatives were examined by measuring gastric acid secretion. Stimulation of gastric acid secretion by these derivatives after intravenous administration was stronger than with native TG. When the acetyl- and caproyl-derivatives were administered into the large intestinal loops, a marked increase in gastric acid secretion was observed in comparison with TG, while no significant effect occurred following administration of the TG derivatives into the small intestines. These results indicated that chemical modification of TG with fatty acids improves the absorption of TG from the large intestines.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
S. S. Davis. Advanced delivery systems for peptides and proteins-pharmaceutical considerations. In S. S. Davis, L. Illum, and E. Tomlinson (eds.), Delivery Systems for Peptide Drugs, Plenum Press, New York, 1986, pp. 1–21.
S. Muranishi. Absorption enhancers. Crit. Rev. Ther. Drug Carrier Syst. 7:1–33 (1990).
V. H. L. Lee and A. Yamamoto. Penetration and enzymatic barriers to peptide and protein absorption. Adv. Drug Del. Rev. 4:171–207 (1990).
H. Bundgaard and J. Møss. Prodrug of peptides. 6. Bioreversible derivatives of thyrotropin-releasing hormone (TRH) with increased lipophilicity and resistance to cleavage by the TRH-specific serum enzyme. Pharm. Res. 7:885–892 (1990).
J. Møss, A. Buur, and H. Bundgaard. Prodrug of peptides. 8. In vitro study of intestinal metabolism and penetration of thyrotropin-releasing hormone (TRH) and its prodrug. Int. J. Pharm. 66:183–191 (1990).
M. Hashimoto, K. Takada, Y. Kiso, and S. Muranishi. Synthesis of palmitoyl derivatives of insulin and their biological activities. Pharm. Res. 6:171–176 (1989).
S. Muranishi, A. Sakai, K. Yamada, M. Murakami, K. Takada, and Y. Kiso. Lipophilic peptides: Synthesis of lauroyl-thyrotropine-releasing hormone and its biological activities. Pharm. Res. 8:649–652 (1991).
S. Muranishi, M. Murakami, M. Hashidzume, K. Yamada, S. Tajima, and Y. Kiso. Trials of lipid modification of peptide hormones for intestinal delivery. J. Control. Release 19:179–188 (1992).
M. Hashizume, T. Douen, M. Murakami, A. Yamamoto, K. Takada, and S. Muranishi. Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats. J. Pharm. Pharmacol. 44:555–559 (1992).
K. Yamada, M. Murakami, A. Yamamoto, K. Takada, and S. Muranishi. Improvement of intestinal absorption of thyrotropin-releasing hormone by chemical modification with lauric acid. J. Pharm. Pharmacol. 44:717–721 (1992).
J. S. Morley, H. L. Tracy, and R. A. Gregory. Structure-function relationships in the active C-terminal tetrapeptide sequence of gastrin. Nature 207:1356–1359 (1965).
H. M. Jennewein, F. Waldeck, and W. Konz. The absorption of tetragastrin from different sites in rats and dogs. Arzneim.-Forsch. (Drug Res.) 24:1225–1228 (1974).
L. Laster and J. H. Walsh. Enzymatic degradation of C-terminal tetrapeptide amide of gastrin by mammalian tissue extracts. Fed. Proc. 27:1328–1330 (1968).
J. H. Walsh and L. Laster. Enzymatic deamidation of the C-terminal tetrapeptide amide of gastrin by mammalian tissues. Biochem. Med. 8:432–449 (1973).
Y. Lapidot, S. Rapport, and Y. Wolman. Use of esters of N-hydroxysuccinimide in the synthesis of N-acylamino acids. J. Lipid Res. 8:142–145 (1967).
M. N. Ghosh and H. O. Schild. Continuous recording of gastric secretion in the rat. Br. J. Pharmacol. 13:54–61 (1958).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tenma, T., Yodoya, E., Tashima, S. et al. Development of New Lipophilic Derivatives of Tetragastrin: Physicochemical Characteristics and Intestinal Absorption of Acyl-tetragastrin Derivatives in Rats. Pharm Res 10, 1488–1492 (1993). https://doi.org/10.1023/A:1018983511247
Issue Date:
DOI: https://doi.org/10.1023/A:1018983511247