2012
DOI: 10.1124/jpet.111.191122
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Pharmacologic Targeting of Bacterial β-Glucuronidase Alleviates Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy in Mice

Abstract: Small intestinal mucosal injury is a frequent adverse effect caused by nonsteroidal anti-inflammatory drugs (NSAIDs). The underlying mechanisms are not completely understood, but topical (luminal) effects have been implicated. Many carboxylic acid-containing NSAIDs, including diclofenac (DCF), are metabolized to acyl glucuronides (AGs), and/or ether glucuronides after ring hydroxylation, and exported into the biliary tree. In the gut, these conjugates are cleaved by bacterial ␤-glucuronidase, releasing the pot… Show more

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Cited by 175 publications
(141 citation statements)
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“…Another possibility is that the diclofenac molecules suppress secretion of mucus, making the anastomosis more vulnerable to leakage, as was recently suggested by Bosmans and colleagues24. Although diclofenac is excreted largely as DAG, this metabolite is reactivated by bacterial glucuronidase in the terminal ileum, where it can cause mucosal damage12 25. In the present study, the acyl‐glucuronide metabolite (DAG) was also abundant in bile.…”
Section: Discussionsupporting
confidence: 61%
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“…Another possibility is that the diclofenac molecules suppress secretion of mucus, making the anastomosis more vulnerable to leakage, as was recently suggested by Bosmans and colleagues24. Although diclofenac is excreted largely as DAG, this metabolite is reactivated by bacterial glucuronidase in the terminal ileum, where it can cause mucosal damage12 25. In the present study, the acyl‐glucuronide metabolite (DAG) was also abundant in bile.…”
Section: Discussionsupporting
confidence: 61%
“…In the present study, the acyl‐glucuronide metabolite (DAG) was also abundant in bile. Reactivation of this metabolite in the gut together with biliary excretion of unconjugated forms of diclofenac may lead to high enteral accumulation of potentially harmful drug molecules, which may jeopardize healing from the luminal side of the anastomosis17 25.…”
Section: Discussionmentioning
confidence: 99%
“…Diclofenac-induced enteropathy was assessed as previously described [22] . The excised small intestine was divided into four segments of approximately equal length and opened longitudinally along the antimesenteric side.…”
Section: Assessment Of Diclofenac-induced Enteropathymentioning
confidence: 99%
“…The contents of the proximal small intestine, the distal small intestine and the ileal valve were collected and mixed with PBS (pH 5.5) in an ice-water bath, and an appropriate dilution was made based on a preliminary experiment. The intestinal β-glucuronidase activity, defined as diclofenac formation from DC-AG, was measured according to a previously described method [22,31] with minor modifications. Briefly, the reaction was initiated by the addition of 100 μL of intestinal content solution pre-incubated at 37 °C in a reaction tube containing DC-AG (final level: 10 μmol/L).…”
Section: Effects Of Ciprofloxacin On Biliary Excretion Of Diclofenacmentioning
confidence: 99%
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