Effect of Oral Pretreatment with Indomethacin on the Intestinal First-Pass Metabolism of Salicylamide in Rabbits

The effect of oral pretreatment with indomethacin on the intestinal first-pass metabolism of salicylamide (SAM) was studied in rabbits using in situ intestinal sacs with complete mesenteric venous blood collection. The appearance of both SAM and its metabolites into the mesenteric venous blood was measured directly by cannulating the mesenteric vein of exposed rabbit intestine and collecting all venous blood draining from the absorbing region. By oral pretreatment with indomethacin, the total amounts of SAM absorbed in 20 and 120 min were significantly increased compared to the control. These results indicated the alteration of the permeability in the intestinal mucosa. In 20 min, indomethacin pretreatment resulted in increased appearance of SAM and SAM glucuronide in the mesenteric venous blood. In 120 min, increased appearance of SAM and decreased appearance of SAM sulfate were observed, compared to the control. These findings suggested that the change in the intestinal first-pass metabolism of SAM is probably due to the intestinal mucosal damage by oral pretreatment with indomethacin.