PubMed1986
Rats were given a single intragastric administration of the prodrug sulindac (4.0 mg/kg) or its sulfide (1.0, 2.0, 4.0, or 8.0 mg/kg) or sulfone (1.0, 2.0, 4.0, or 8.0 mg/kg) metabolites and were then subjected to acute stress in the form of immobilization for 3 hr in a cold environment. Control rats received an equal volume of propylene glycol vehicle or nothing po. Other rats received 200 mg/kg acetylsalicylic acid (ASA) with or without stress, to compare the gastrointestinal effects of sulindac metabolites with those of a known non-steroidal anti-inflammatory agent. The sulfide metabolite exacerbated stress-induced gastric glandular ulcer incidence and severity in a dose-related manner relative to all groups except the ASA-stress group, which exhibited the greatest amount of gastric damage. The sulfone metabolite did not potentiate ulcer incidence or severity beyond control (stress only) levels at lower doses. However, at 4.0 and 8.0 mg/kg, the observed ulceration was greater than that seen in stressed but otherwise untreated animals. Sulindac, vehicle, and otherwise untreated rats exhibited a similar degree of stress-induced gastric damage. It appears that the prodrug does not significantly enhance stress-related gut disease, but that the active sulfide metabolite does. Although the clinical literature suggests that the sulfone metabolite is inactive, the present results suggest otherwise. While this metabolite did not, by itself, induce gastric damage at higher doses, sulfone did exacerbate stress ulcer formation. This is the only report of which we are aware, indicating a possible toxic effect of the sulfone metabolite.