Drug enterocyte adducts: Possible causal factor for diclofenac enteropathyin rats

Background & Aims: Enteropathy is a frequent complication of diclofenac and other nonsteroidal anti-inflammatory drugs, yet little is known about the underlying mechanism. One possibility is that reactive metabolites of diclo fenac form adducts with enterocyte macromolecules, as previously shown for liver. We addressed this possibility by using immunohistochemistry to detec t diclofenac adducts. Methods: Rats were treated ovally with diclofenac (10 -100 mg/kg) and killed after 1-24 hours, and their gastrointestinal (GI) tr acts were evaluated for ulcer number and area. Adduct distribution and inte nsity were assessed by immunohistochemistry by using a technique to simulta neously process and stain multiple intestinal rings. Results: Drug treatmen t led to dose-dependent formation of both adducts and ulcers only in small intestine and only in animals with intact enterohepatic circulation. Adduct s formed within enterocytes by 1 hour, translocated to the brush border, pr eceded ulceration and vascular protein leakage, and were intense at sites o f ulceration. Adducts and ulcers exhibited a parallel distribution within i ntestinal quintiles: 3rd > 5th >> 1st. Conclusions: Diclofenac treatment re sulted in the formation of drug adducts in enterocytes. Because this molecu lar change occurred before ulceration, was dose dependent, and exhibited co ncordant distribution with extent of ulceration, the results suggest a caus al role for drug adduct formation in diclofenac enteropathy.