Background & aims: Enterohepatic recirculation of nonsteroidal anti-inflammatory drugs is a critical factor in the pathogenesis of intestinal injury, but the underlying mechanism of toxicity remains obscure. The aim of this study was to examine the role of diclofenac acyl glucuronide, which is the major biliary metabolite and is chemically reactive, in the precipitation of small intestinal ulceration.
Methods: Hepatocanalicular conjugate export pump-deficient (TR-) rats were used to selectively block diclofenac enterohepatic circulation without interrupting bile flow. Bile from diclofenac-treated normal rats was orally transferred to wild-type and TR- rats, and the extent of ulcer formation was compared with that induced by control bile containing free diclofenac. The effect of induction of hepatic diclofenac glucuronosyltransferase on the severity of diclofenac-induced ulceration was also determined.
Results: TR- rats were refractory to diclofenac given either intraperitoneally or perorally. However, transfer of bile containing diclofenac glucuronide significantly increased the extent of ulcer formation in both normal and TR- rats. Moreover, induction of glucuronosyltransferase aggravated intestinal ulceration.
Conclusions: The reactive acyl glucuronide of diclofenac, or the acyl glucuronide of one of its oxidative metabolites, is directly involved in the pathogenesis of small intestinal injury.