NSAID Acyl Glucuronides and Enteropathy.

Summary of "NSAID Acyl Glucuronides and Enteropathy."

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acid-containing compounds that are conjugated in the liver to acyl glucuronides and excreted across the hepatocanalicular membrane into bile. Chronic and acute NSAID use has not only been associated with gastric injury but also increasingly recognized to cause small intestinal injury (enteropathy). The mechanisms of NSAID enteropathy are still unknown, but a combination of topical effects (including mitochondrial injury) combined with inhibition of COX1/2, followed by an inflammatory response triggered by LPS-mediated activation of LTR4 on macrophages, have been implicated in the pathogenesis. Some of the nucleophilic proteins that are targeted by the electrophilic NSAID acyl glucuronides or their iso-glucuronides have been identified both in bile canaliculi and on the apical membrane domain of enterocytes (e.g., aminopeptidase N); however, the mechanistic role of covalent adducts has remained enigmatic. In contrast, it has become increasingly clear that acyl glucuronide formation is a major toxicokinetic determinant, in that the drug conjugates are a transport form delivering the drug to the more distal parts of the jejunum/ileum, where the glucuronic acid moiety is cleaved off the aglycone due to higher local pH and the presence of bacterial β-glucuronidase. Through this mechanism, high local concentrations of the parent NSAID can be attained, potentially leading to local tissue injury. Thus, even if one considers the formation of acyl glucuronides not as a potentially dangerous toxophore by virtue of their protein-reactivity, acyl glucuronides could still be a red flag in drug development if excreted at high rates into bile and delivered to more distal areas of the small intestine where high amounts of parent drug is released.


Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, 69 North Eagleville Road Unit 3092, Storrs, CT 06269-3092, USA.

Journal Details

This article was published in the following journal.

Name: Current drug metabolism
ISSN: 1875-5453


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Medical and Biotech [MESH] Definitions

An NAD-dependent enzyme that catalyzes the oxidation of acyl-[acyl-carrier protein] to trans-2,3-dehydroacyl-[acyl-carrier protein]. It has a preference for acyl groups with a carbon chain length between 4 to 16.

An enzyme that catalyzes the oxidation of acyl-[acyl-carrier protein] to trans-2,3-dehydroacyl-[acyl-carrier protein] in the fatty acid biosynthesis pathway. It has a preference for acyl derivatives with carbon chain length from 4 to 16.

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An enzyme of long-chain fatty acid synthesis, that adds a two-carbon unit from malonyl-(acyl carrier protein) to another molecule of fatty acyl-(acyl carrier protein), giving a beta-ketoacyl-(acyl carrier protein) with the release of carbon dioxide. EC

Consists of a polypeptide chain and 4'-phosphopantetheine linked to a serine residue by a phosphodiester bond. Acyl groups are bound as thiol esters to the pantothenyl group. Acyl carrier protein is involved in every step of fatty acid synthesis by the cytoplasmic system.

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