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.