STIMULATION OF PROSTAGLANDIN BIOSYNTHESIS MEDIATES GASTROPROTECTIVE EFFECT OF REBAMIPIDE IN RATS

The concept that gastroprotection by agents such as mild irritants, an tacids, or sucralfate is prostaglandin (PG)-mediated has been challeng ed recently. These agents do not reproducibly stimulate prostaglandin formation, and indomethacin does not effectively attenuate their prote ctive potency. Rebamipide is a novel antiulcer compound. This study wa s designed to clarify whether eicosanoids contribute to the gastroprot ective activity of the drug. In the rat stomach, rebamipide (100 and 5 00 mg/kg, intraperitoneally) slightly increased release of PGE2, 6-ket o-PGF1alpha, thromboxane B2, and the metabolite 15-keto-13,14-dihydro- PGE2 from mucosal fragments incubated ex vivo and significantly enhanc ed secretion of these products into the lumen, resulting in gastric ju ice eicosanoid levels exceeding those in controls several-fold. Mucosa l formation of leukotriene (LT) C4 was not affected by rebamipide. Reb amipide caused substantial protection against gastric damage produced by ethanol, which was antagonized by pretreatment with indomethacin (0 .1-5 mg/kg, subcutaneously). The. dose-response relationship of indome thacin for inhibition of prostaglandin formation and rebamipide-induce d protection correlated well and 5 mg/kg indomethacin completely preve nted the protective effect of rebamipide. The results indicate that. ( 1) in contrast to most other protective agents, protection by rebamipi de involves the endogenous prostaglandin system; (2) the increase in p rostaglandin formation results from stimulation of biosynthesis, and n ot inhibition of degradation; (3) gastroprotection by rebamipide occur s despite increased thromboxane formation and is not associated with r educed generation of LTC4; and (4) determinations of gastric juice eic osanoids seem to be particularly useful to evaluate effects of agents increasing formation of cyclooxygenase products in the stomach.