Importance of biliary excretion of indomethacin in gastrointestinal and hepatic injury

Dial, Elizabeth J.; Darling, Rebecca; Lichtenberger, Lenard M.

doi:10.1111/j.1440-1746.2007.05266.x

Cited by 20 publications

(19 citation statements)

References 25 publications

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“…Naproxen is excreted in bile and undergoes extensive enterohepatic circulation. Treatment with naproxen significantly increased the cytotoxic effects of bile on cultured intestinal epithelial cells, consistent with effects seen with other NSAIDs in similar models (12,64). In contrast to the effects of naproxen, treatment of rats with ATB-346, an H 2 S-releasing derivative of naproxen, did not elicit intestinal damage or inflammation.…”

Section: Discussionsupporting

confidence: 79%

Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID

Blackler

Palma

Mańko

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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The small intestine is a significant site of ulceration and bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis is poorly understood. The present study explored the roles of bile, bacteria, and enterohepatic circulation to NSAID enteropathy, using both a conventional NSAID (naproxen) and a gastrointestinal-safe naproxen derivative (ATB-346), as well as proton pump inhibitors (PPIs). Rats were treated orally with naproxen or equimolar doses of ATB-346 over a 5-day period, with or without PPI administration, and intestinal damage was quantified. The cytotoxicity of bile from the rats was evaluated in vitro. Biliary excretion of naproxen and ATB-346 was determined. The impact of the NSAIDs and of PPIs on the composition of the intestinal microbiota was examined by deep sequencing of 16s rRNA. Naproxen caused significant intestinal damage and inflammation, whereas ATB-346 did not. Naproxen, but not ATB-346, dose dependently increased the cytotoxicity of bile, and it was further increased by PPI coadministration. Whereas biliary excretion of naproxen was significant in naproxen-treated rats, it was greatly reduced in rats treated with ATB-346. The enteric microbiota of naproxen-treated rats was distinct from that in vehicle- or ATB-346-treated rats, and PPI administration caused significant intestinal dysbiosis. The increase in cytotoxicity of bile induced by naproxen and PPIs may contribute significantly to intestinal ulceration and bleeding. Some of these effects may occur secondary to significant changes in the jejunal microbiota induced by both naproxen and PPIs.

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Section: Discussionsupporting

confidence: 79%

Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID

Blackler

Palma

Mańko

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This toxicity of Indo with bile acids has also been shown in vitro cell systems [12]. The cytotoxic action of NSAIDs in combination with natural bile and/or synthetic bile acids can be reversed in a dose-dependent fashion by the addition of phosphatidylcholine [38]. Therefore, it follows that indomethacin that is pre-associated with PC (Indo-PC) may have less GI toxicity than the NSAID alone.…”

Section: Discussionmentioning

confidence: 90%

In vitro and in vivo Protection against Indomethacin-Induced Small Intestinal Injury by Proton Pump Inhibitors, Acid Pump Antagonists, or Indomethacin-Phosphatidylcholine

Lim¹,

Phan

Dial

et al. 2012

Digestion

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Background/Aims: Proton pump inhibitors (PPIs) are widely used to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcers. NSAIDs produce small intestinal injury and some PPIs have been reported to protect against NSAID-induced small bowel injury in rats. The aim of this study was to compare PPIs, revaprazan, and phosphatidylcholine-associated indomethacin (Indo-PC) for protection against indomethacin (Indo)-induced small bowel injury. Methods: Rat intestinal epithelial cells (IEC-6) were pretreated with omeprazole, lansoprazole, or revaprazan prior to exposure to Indo or Indo-PC. Cell viability was assessed by methyl thiazolyl tetrazolium assay. Omeprazole, lansoprazole, or revaprazan was administered orally to rats prior to the vehicle or Indo. Indo-PC was administered alone. After 24 h, small intestinal erosions were counted; intestinal bleeding was assessed as the hemoglobin concentration of small intestinal fluid. Results: Omeprazole, lansoprazole, and revaprazan did not protect against Indo-induced IEC-6 cell injury. Indo-PC was less damaging in vitro than Indo alone. In vivo, neither omeprazole nor lansoprazole protected against Indo-induced small bowel injury; however, revaprazan pretreatment and Indo-PC resulted in significantly fewer erosions (>50% reduction) or bleeding (>80% reduction). Conclusion: PPIs showed no small bowel protective effect in vitro or in vivo. Revaprazan showed a small bowel protective effect in vivo, whereas Indo-PC was protective both in vitro and in vivo.

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“…Therefore, NSAIDs secreted in bile interact with its amphipathic components, such as phosphatidylcholine and bile acids; this leads to an alteration of the structure and the stability of these components, and consequently the toxicity of bile in the small intestine is modified[56]. Dial et al[57] examined the biliary phosphatidylcholine (PC), which appears to have protective effects on enterocytes, cholangiocytes and erythrocytes against damage induced by bile salts. NSAIDs appear to determine intestinal damage in proportion to their ability to be secreted via the bile because of their capacity to chemically bind with the micelles and with the PC, lowering their effects.…”

Section: Pathogenesis Of Nsaid Enteropathymentioning

confidence: 99%

“…As previously mentioned, NSAIDs bind the PC and this process takes place in the gastrointestinal tract, where the drug-induced loss of PC, which protects the mucosa, causes mucosal damage. The PC would protect it from both damage induced by bile salts and by NSAIDs[57,58]. …”

Section: Pathogenesis Of Nsaid Enteropathymentioning

confidence: 99%

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

Utzeri

Usai

2017

WJG

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The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

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Importance of biliary excretion of indomethacin in gastrointestinal and hepatic injury

Cited by 20 publications

References 25 publications

Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID

Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID

In vitro and in vivo Protection against Indomethacin-Induced Small Intestinal Injury by Proton Pump Inhibitors, Acid Pump Antagonists, or Indomethacin-Phosphatidylcholine

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

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