ABSTRACT-We investigated the in vivo antagonistic activity of ONO-1078 against peptide leuko trienes (LTs) in guinea pigs. ONO-1078, when administered p.o. (0.3-3 mg/kg), caused a dose-depend ent reduction of LTC4-, LTD4 and LTE4-induced bronchoconstriction, LTD4-induced airway micro vascular leakage and LTD4-induced increase in cutaneous vascular permeability. When administered in travenously, ONO-1078 (3 30 ,u g/kg) inhibited these responses approximately 200 600 fold more potently than FPL55712. When guinea pigs were treated with indomethacin to examine the antagonism of ONO-1078 on the direct action against peptide LTs, intravenous (3 30 ,u g/kg) and oral (0.3-3 mg/kg) administration of ONO-1078 also inhibited LTC4 and LTD4-induced bronchoconstriction, and its activity was approximately 300 500 fold more potent than that of FPL55712. ONO-1078 (10 mg/kg, i.v.) had no inhibitory effect on bronchoconstrictions induced by histamine, acetylcholine, serotonin, arachidonic acid, LTB4, prostaglandin (PG) F2a , PGD2, 9a ,11,Q-PGF2, a stable thromboxane A2 mi metic agent and platelet activating factor. Furthermore, oral administration of ONO-1078 (1-10 mg/kg) inhibited slow-reacting substance of anaphylaxis mediated bronchoconstriction induced by antigen in a dose-dependent manner. These results indicate that ONO-1078 is an extremely potent, selective and orally active peptide LT antagonist and that oral administration of ONO-1078 antagonizes not only ex ogenously administered peptide LTs but also endogenous peptide LTs.

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