Gastroenterology

Gastroenterology

Volume 115, Issue 6, December 1998, Pages 1476-1482
Gastroenterology

Alimentary Tract
Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats☆,☆☆

https://doi.org/10.1016/S0016-5085(98)70026-5Get rights and content

Abstract

Background & Aims: Enterohepatic recirculation of nonsteroidal anti-inflammatory drugs is a critical factor in the pathogenesis of intestinal injury, but the underlying mechanism of toxicity remains obscure. The aim of this study was to examine the role of diclofenac acyl glucuronide, which is the major biliary metabolite and is chemically reactive, in the precipitation of small intestinal ulceration. Methods: Hepatocanalicular conjugate export pump-deficient (TR−) rats were used to selectively block diclofenac enterohepatic circulation without interrupting bile flow. Bile from diclofenac-treated normal rats was orally transferred to wild-type and TR− rats, and the extent of ulcer formation was compared with that induced by control bile containing free diclofenac. The effect of induction of hepatic diclofenac glucuronosyltransferase on the severity of diclofenac-induced ulceration was also determined. Results: TR− rats were refractory to diclofenac given either intraperitoneally or perorally. However, transfer of bile containing diclofenac glucuronide significantly increased the extent of ulcer formation in both normal and TR− rats. Moreover, induction of glucuronosyltransferase aggravated intestinal ulceration. Conclusions: The reactive acyl glucuronide of diclofenac, or the acyl glucuronide of one of its oxidative metabolites, is directly involved in the pathogenesis of small intestinal injury.

GASTROENTEROLOGY 1998;115:1476-1482

Section snippets

Chemicals

Diclofenac sodium was purchased from Sigma Chemical Co. (Buchs, Switzerland). 3,4-Benzoquinoline (phenanthridine) was obtained from Aldrich (Buchs, Switzerland). All other chemicals were obtained from Sigma or Fluka Chemie AG (Buchs, Switzerland) and were of the highest grade available.

Animals and treatments

Permission for animal studies was obtained from the local regulatory authorities, and all study protocols were in compliance with institutional guidelines. Female CRL:(Wi)BR Wistar rats, 10–12 weeks of age, were

Diclofenac-induced small intestinal ulceration

A single intraperitoneal administration of diclofenac readily induced mucosal damage to the small intestine in wild-type Wistar rats. This reaction was clearly dose-dependent (Figure 1).

. Dose-dependent small intestinal ulceration in Wistar rats 24 hours after a single intraperitoneal administration of diclofenac. The lesions were categorized according to size as <1 mm long (■), 1–5 mm (▨), 5–10 mm (▨), and >10 mm (□). Inset, Total ulcer length in response to different diclofenac doses. Data are

Discussion

The aim of this study was to test the hypothesis that the reactive diclofenac acyl glucuronide, which is the major biliary metabolite of diclofenac, might play a direct role in NSAID enteropathy. Our results show that diclofenac glucuronide, rather than the aglycone, is associated with increased ulceration in the rat jejunum and ileum. We conclude that the interaction of the reactive diclofenac glucuronide with enterocytes might be involved in initiation of diclofenac-induced damage to the

Acknowledgements

The authors thank Dr. U. Zweifel, ETH, for his expert assistance with the high-performance liquid chromatography analyses.

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    ☆

    Address requests for reprints to: Urs A. Boelsterli, Ph.D., F. Hoffmann-LaRoche AG, PRNT, Building 73/103a, CH-4070 Basel, Switzerland. e-mail: [email protected]; fax: (41) 61-688-8101.

    ☆☆

    Supported in part by the Swiss National Science Foundation (grant 32.40480.94 to U.A.B.).

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    Copyright © 1998 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.