Fenflumizole: Interactions with the Arachidonic Acid Cascade

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Abstract
Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new nonsteroidal antiinflammatory agent, was investigated for interferences with cyclo-oxygenase activity in vivo, ex vivo and in vitro in comparison with indomethacin (and aspirin). Fenflumizole was comparable to indomethacin ex vivo in inhibition of thromboxane (TX)A2 production in rabbit platelets and inhibition of prostaglandin (PG)I2 (.apprx. prostacyclin) generation in rabbit mesenteric arteries and in vivo as an inhibitor of PGE2 formation in inflammatory exudates in rats. Fenflumizole was 18 times less active than indomethacin in inhibition of PGE2 synthesis in vitro and 170 times weaker as an inhibitor of PGI2 generation in the rat stomach mucosa ex vivo. Fenflumizole was 20-50 times more potent than indomethacin in vivo in inhibition of arachidonic acid induced bronchoconstriction in guinea pigs, in inhibition of platelet aggregation on tendons superfused with blood from rabbits and in vitro in inhibition of aggregation of human and rabbit platelets. Neither fenflumizole nor indomethacin inhibited TXA2-synthetase in vitro. Aspirin, when tested, was less potent than fenflumizole and indomethacin. Fenflumizole apparently is a potent cyclo-oxygenase inhibitor. The very potent activity of fenflumizole against platelet and bronchoconstriction suggests a selectivity in the mode of action. The weak inhibition of gastric PGI2 generation may account for the previously observed weak gastroulcerogenicity of fenflumizole.