An assessment of 5-fluorouracil (5-FU)-induced mucosal damage in vivo by measuring the metabolism of salicylamide (SAM) was investigated in rabbit intestine. The mucosal damage in the intestine 48 h after oral administration of 5-FU (30 mg/kg) was examined using a scanning electron microscope. By the oral pretreatment with 5-FU, the morphological changes of jejunal and ileal mucosa were recognized compared with the control. The intestinal first-pass metabolism of SAM was studied 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 intestine and collecting all venous blood draining from the absorbing region. Following oral pretreatment with 5-FU, the appearance of SAM glucuronide (SAMG) in the mesenteric venous blood was significantly increased. The increased blood concentration of SAMG following intraduodenal administration of SAM in vivo was observed in rabbits pretreated with 5-FU orally. However, the blood concentration of SAMG after intravenous administration of SAM was not increased compared with the control. These findings suggest that the change in intestinal first-pass metabolism of SAM may be due to the intestinal mucosal damage by oral pretreatment with 5-FU. The alteration of intestinal first-pass metabolism of a marker compound may be utilized for the assessment of intestinal mucosal damage in vivo.

The gastrointestinal mucosal damage following the oral administration of salicylic acid or salicyluric acid was examined in rabbits using a scanning electron microscope. Six and 24 h after treatment with salicylic acid, morphological changes of gastric mucosa were recognized. In rabbits treated with salicyluric acid, however, severe damage in the gastric mucosa was not found after 24 h compared with the treatment with salicylic acid. Following the treatment with salicylic acid, some mucosal damage in the duodenum, jejunum and ileum was observed after 24 h. The surface character of the duodenal, jejunal, ileal, caecal and colonic mucosa were almost identical compared with the control following the treatment with salicyluric acid. It was reported that salicyluric acid is metabolized to salicylic acid by the intestinal microorganisms. From these results, it was suggested that prodrugs utilizing the metabolism of salicyluric acid to salicylic acid by intestinal microorganisms may be useful in reducing gastrointestinal mucosal damage.

Indomethacin-induced mucosal damage was assessed in vivo by measuring salicylamide (SAM) metabolism in rabbit intestine. Intestinal mucosal damage 48 h after oral indomethacin (500 mg/kg) administration was examined using a scanning electron microscope. Duodenal, jejunal and ileal mucosal toxicity was compared with that in controls. Intestinal first-pass metabolism of SAM was studied using in situ intestinal sacs with intact mesenteric venous blood collection. The appearance of both SAM and its metabolites in the mesenteric venous blood was measured following cannulation of the mesenteric vein of the exposed intestine and collecting all venous blood draining from the absorbing region. Following oral pretreatment with indomethacin, the appearance of SAM and SAM glucuronide (SAMG) in the mesenteric venous blood was significantly increased. The concentrations of SAM and SAMG in the blood increased following intraduodenal administration of SAM in vivo in rabbits orally pretreated with indomethacin compared with controls. However, after intravenous administration of SAM, the blood concentration of SAM and SAMG was not increased compared with controls. These findings suggest that the differences in intestinal first-pass metabolism of SAM may be due to the intestinal mucosal damage induced by oral indomethacin pretreatment. The results indicate that the alteration of intestinal first-pass metabolism of a marker compound may be utilized to assess intestinal mucosal damage in vivo.