Fenbufen and biphenylacetic acid inhibit platelet function and the arachidonate prostaglandin system

Abstract

Biphenylacetic acid or BPAA ([1,1-biphenyl]-4-acetic acid) is a metabolite of the non-steroidal anti-inflammatory drug, fenbufen (γ-oxo[1,1-biphenyl]-4-butanoic acid). A 0.12 mM concentration of BPAA produces almost complete inhibition of arachidonate-induced aggregation in vitro comparable to the effect produced by similar concentration of other non-steroidal anti-inflammatory agents. Fenbufen does not inhibit arachidonate-induced aggregation in vitro . These data correlate with the ability of BPAA, but not fenbufen, to inhibit platelet prostaglandin synthetase in vitro . Respiratory distress and histologic evidence of platelet aggregates formed in the pulmonary microvasculature following arachidonate infusion are markedly inhibited by oral doses of both fenbufen and BPAA. The order of efficacy (at 10 mg/kg) for inhibition of respiratory distress is BPAA > fenbufen > aspirin. These data confirm other studies indicating metabolic conversion of fenbufen in vivo to the active metabolite, BPAA. Collagen-induced aggregation is reduced by in vitro addition of either BPAA or fenbufen and in platelet-rich plasma from rats receiving oral doses of these compounds. BPAA added in vitro is more potent than either aspirin or fenbufen as an inhibitor of collagen-induced aggregation. Following in vivo dosing at 10 mg/kg, BPAA is comparable to aspirin in efficacy as an inhibitor of collagen-induced aggregation, while the same dose of fenbufen is less effective. The ability of BPAA to inhibit platelet aggregation appears to be related to intererence with the arachidonate-thromboxane-prostaglandin system. Fenbufen's inhibitory action may be dependent on conversion to BPAA or involve another mechanism. Other data suggest, however, that this mechanism is not related to inhibition of serotonin release or inhibition of phosphodiesterase activity in platelets.