Drug enterocyte adducts: Possible causal factor for diclofenac enteropathy in rats

Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug commonly prescribed to reduce pain in acute and chronic inflammatory diseases. One of the main DCF metabolites is a reactive diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets and may contribute to adverse drug reactions arising from DCF use. Cellular efflux of DCF-AG is partially mediated by multidrug resistanceassociated proteins (Mrp). The importance of Mrp2 during DCFinduced toxicity has been established, yet the role of Mrp3 remains largely unexplored. In the present work, Mrp3-null (KO) mice were used to study the toxicokinetics and toxicodynamics of DCF and its metabolites. DCF-AG plasma concentrations were 90% lower in KO mice than in wild-type (WT) mice, indicating that Mrp3 mediates DCF-AG basolateral efflux. In contrast, there were no differences in DCF-AG biliary excretion between WT and KO, suggesting that only DCF-AG basolateral efflux is compromised by Mrp3 deletion. Susceptibility to toxicity was also evaluated after a single high DCF dose. No signs of injury were detected in livers and kidneys; however, ulcers were found in the small intestines. Furthermore, the observed intestinal injuries were consistently more severe in KO compared with WT. DCF covalent adducts were observed in liver and small intestines; however, staining intensity did not correlate with the severity of injuries, implying that tissues respond differently to covalent modification. Overall, the data provide strong evidence that (1) in vivo Mrp3 plays an important role in DCF-AG disposition and (2) compromised Mrp3 function can enhance injury in the gastrointestinal tract after DCF treatment.

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“…4). The intestinal injury is consistent with published reports on DCF ulcerogenicity (Atchison et al, 2000;Ramirez-Alcantara et al, 2009).…”

Section: Discussionsupporting

confidence: 92%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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“…Although several reports on the development of enteropathy by single dose of diclofenac in animal model exist [37][38][39][40][41] , the dosages of diclofenac used in these studies were much higher than the clinical dosage. The present study showed that rats orally treated with 10 mg/kg of diclofenac (equivalent to a clinical dosage of 120 mg in a 70 kg human) daily for 6 d also developed typical enteropathy.…”

Section: Discussionmentioning

confidence: 99%

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

et al. 2016

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Aim: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which may cause serious intestinal adverse reactions (enteropathy). In this study we investigated whether co-administration of ciprofloxacin affected the pharmacokinetics of diclofenac and diclofenacinduced enteropathy in rats. Methods: The pharmacokinetics of diclofenac was assessed in rats after receiving diclofenac (10 mg/kg, ig, or 5 mg/kg, iv), with or without ciprofloxacin (20 mg/kg, ig) co-administered. After receiving 6 oral doses or 15 intravenous doses of diclofenac, the rats were sacrificed, and small intestine was removed to examine diclofenac-induced enteropathy. β-Glucuronidase activity in intestinal content, bovine liver and E coli was evaluated. Results: Following oral or intravenous administration, the pharmacokinetic profile of diclofenac displayed typical enterohepatic circulation, and co-administration of ciprofloxacin abolished the enterohepatic circulation, resulted in significant reduction in the plasma content of diclofenac. In control rats, β-glucuronidase activity in small intestinal content was region-dependent: proximal intestine

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“…This merits special attention because most NSAIDs, including DCLF, have been associated in humans with GI injury, and the latter can promote LPS and/or bacterial translocation from the intestine into the circulation. In laboratory rodents a single, small dose of DCLF (1.5 mg/kg) induced intestinal ulceration Atchison et al, 2000). Moreover, DCLF is normally prescribed to patients with inflammatory conditions, in which inflammatory mediators are usually present.…”

Section: B Diclofenac-induced Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

et al. 2009

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Drug enterocyte adducts: Possible causal factor for diclofenac enteropathy in rats

Cited by 65 publications

References 28 publications

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

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