Aggravation by Clopidogrel, An Antiplatelet Drug, of Antral Damage Induced by NSAID in Rats: A Prophylactic Effect of Antiulcer Drugs

Abstract

Recent studies suggested a risk of gastric adverse reaction on the concomitant use of antithrombotic drugs with NSAIDs. We investigated whether clopidogrel, a P2Y12 receptor antagonist, aggravates antral damage induced in rats by indomethacin and examined the effects of several antiulcer drugs on these lesions. Male SD rats fasted for 24 h were refed for 1 h, and then administered indomethacin (30 mg/kg) s.c. 1 h after refeeding, and the stomachs were examined for lesions 6 h thereafter. Clopidogrel (3‐30 mg/kg) was given p.o. 3 times, 48, 24 h and 30 min before indomethacin. Famotidine or teprenone was given p.o. 1 h before indomethacin. Indomethacin alone produced damages, mostly nonhemorrhagic lesions, in the antrum of refed rats. Clopidogrel dose‐dependently worsened these lesions with convertion of nonhemorrhagic damages into hemorrhagic ones. The ulcerogenic response to indomethacin plus clopidogrel (30 mg/kg) was significantly suppressed by pretreatment with famotidine with a decrease in hemorrhagic lesions. The aggravating effect of clopidogrel was also attenuated by teprenone, though the effect was less pronounced than that of famotidine. These results suggest that 1) clopidogrel aggravates NSAID‐induced antral lesions, converting from nonhemorrhagic into hemorrhagic damage, and 2) these lesions are effectively prevented by both antisecretory and mucosal protective drugs.