REACTIVE ACYL GLUCURONIDES: POSSIBLE ROLE IN SMALL INTESTINAL TOXICITY INDUCED BY NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Small intestinal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) has gained increasing attention in the past years. The mechanism underlying NSAID enteropathy has remained elusive but may be different from that in the stom ach. Three important factors include the presence of bile or biliary constituents, enterohepatic circulation of NSAIDs, and enteric bacteria. This article summarizes new lines of evidence indicating that acyl glucuronides, which are m etabolites of many carboxylic acid NSAIDs, m ay be causally linked with small intestinal ulceration. Acyl glucuronides are form ed in the liver; excreted into thebiliary treeby the conjugate export pump, Mrp2;and subsequently delivered to the lower intestine. Acyl glucuronides are chemically reactive and can covalently modify a number of target proteins in the liver, biliary tree, and intestine. The following article focuses on the positive correlation between the degree by which the small intestine is exposed to NSAID acyl glucuronides and...