Skip to main content
SpringerLink
Log in

Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability

  • Original Articles
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

In previous open studies, misoprostol and metronidazole reduced nonsteroidal anti-inflammatory drug-induced intestinal permeability changes and inflammation respectively. We assessed the effects of indomethacin treatment (50 mg three times a day) for one week with either coadministered metronidazole (400 mg twice a day, group 1,N=9) or misoprostol (200 μg four times a day, group 2,N=7) on intestinal permeability to [51Cr]EDTA and mannitol in healthy volunteers, using double-blind, placebo-controlled, randomized techniques. Given alone, neither metronidazole nor misoprostol affected [51Cr]EDTA permeation, whereas indomethacin alone increased it from 1.20 (0.40) [mean percent urinary recovery (sd) groups 1 and 2] to 2.43 (0.72),P<0.002. Coadministered metronidazole (group 1) prevented this increase [1.10 (0.39) before, 1.55 (0.54) after,P>0.05], whereas misoprostol (group 2) did not [1.31 (0.51) before, 3.26 (1.10) after,P=0.005]. No drug regimen altered mannitol permeation. Indomethacin and misoprostol did not affect urinary recovery of intravenously administered probes. The results with metronidazole, if related to its antibacterial effects, support evidence from animal models that bacteria contribute to NSAID-induced intestinal damage. The previously reported reduction of indomethacin-induced increased permeability by misoprostol during a one-day study is not seen when the drugs are used in standard clinical doses for one week.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Davies GR, Rampton DS: The pro-drug sulindac may reduce the risk of intestinal damage associated with the use of conventional non-steroidal antiinflammatory drugs. Aliment Pharmacol Ther 5:593–598, 1991

    Google Scholar 

  2. Bjarnason I, Fehilly B, Smethurst P, Menzies IS, Levi AJ: Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man. Gut 32:275–277, 1991

    Google Scholar 

  3. Bjarnason I, So A, Levi AJ, Peters TJ, Williams P, Zanelli GD, Gumpel JM, Ansell B: Intestinal permeability and inflammation in rheumatoid arthritis: Effects of non-steroidal anti-inflammatory drugs. Lancet ii:1171–1174, 1984

    Google Scholar 

  4. Jenkins RT, Rooney PJ, Jones DB, Bienenstock, J, Goodacre RL: Increased intestinal permeability in patients with rheumatoid arthritis: A side effect of oral nonsteroidal anti-inflammatory drug therapy? Br J Rheumatol 26:103–107, 1987

    Google Scholar 

  5. Morris AJ, Madhok R, Sturrock RD, Capell HA, MacKenzie JF: Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs. BMJ 337:520, 1991

    Google Scholar 

  6. Bjarnason I, Peters TJ: Intestinal permeability, non-steroidal antiinflammatory drug enteropathy and inflammatory bowel disease: An overview. Gut Festschrift 30:22–28, 1989

    Google Scholar 

  7. Rampton DS: Nonsteroidal antiinflammatory drugs and the lower gastrointestinal tract. Scand J Gastroenterol 22:1–4, 1987

    Google Scholar 

  8. Sartor RB: Importance of intestinal mucosal immunity and luminal bacterial cell wall polymers in the aetiology of inflammatory joint disease.In Baillières Clinical Rheumatology. PJ Rooney (ed). London, Baillière-Tindall, 1989, pp 223–245

    Google Scholar 

  9. Zaphiropoulos GC: Rheumatoid arthritis and the gut. Br J Rheumatol 25:138–140, 1986

    Google Scholar 

  10. Bourne JT, Kumar P, Huskisson EC, Mageed R, Unsworth DJ, Wojtulewski JA: Arthritis and coeliac disease. Ann Rheum Dis 44:592–598, 1985

    Google Scholar 

  11. Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies IS, Levi AJ: Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci 34:407–411, 1989

    Google Scholar 

  12. Bjarnason I, Smethurst P, Clark P, Menzies I, Levi J, Peters T: Effect of prostaglandin on indomethacin inceased intestinal permeability in man. Scand J Gastroenterol (Suppl) 164:97–103, 1989

    Google Scholar 

  13. Bjarnason I, Williams P, Smethurst P, Peters TJ, Levi AJ: Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 27:1292–1297, 1986

    Google Scholar 

  14. Rooney PJ, Jenkins RT: Nonsteroidal antiinflammatory drugs (NSAIDs) and the bowel mucosa: Changes in intestinal permeability may not be due to changes in prostaglandins. Clin Exp Rheum 8:328–329, 1990

    Google Scholar 

  15. Hallyar J, Somasundaram S, Sarathchandra P, Levi AJ, Bjarnason I: Early cellular events in the pathogenesis of NSAID enteropathy in the rat. Gastroenterology 100:A216, 1991

    Google Scholar 

  16. Bjarnason I: Non-steroidal anti-inflammatory drug-induced small intestinal inflammation in man.In Recent Advances in Gastroenterology, RE Pounder (ed). London, Churchill Livingstone, 1989, pp 23–46.

    Google Scholar 

  17. Rainsford KD: Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. Scand J Gastroenterol (Suppl) 163:9–16, 1989

    Google Scholar 

  18. Rainsford KD: Mechanisms of gastric contrasted with intestinal damage by non-steroidal anti-inflammatory drugs.In Side Effects of Anti-Inflammatory Drugs: Part 2. KD Rainsford, GP Velo (eds). Lancaster, UK, MTP Press, 1987, pp 3–28

    Google Scholar 

  19. Jenkins AP, Trew DR, Crump BJ, Nukajam WS, Foley JA, Menzies IS, Creamer B: Do non-steroidal anti-inflammatory drugs increase colonic permeability? Gut 32:66–69, 1991

    Google Scholar 

  20. Kent TH, Cardelli RM, Stamler FW: Small intestinal ulcers in rats given indomethacin. Am J Pathol 54:237–245, 1969

    Google Scholar 

  21. Robert A, Asano T: Resistance of germ free rats to indomethacin-induced intestinal lesions. Prostaglandins 14:331–341, 1977

    Google Scholar 

  22. Bjarnason I, Hallyar J, Smethurst P, Price A, Gumpel M, Levi J: Studies on the pathogenesis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy in man. Gastroenterology 100:A198, 1991

    Google Scholar 

  23. Bjarnason I, Hopkinson N, Zanelli G, Prouse P, Smethurst P, Gumpel JM, Levi AJ: Treatment of non-steroidal anti-inflammatory drug induced enteropathy. Gut 33:777–780, 1990

    Google Scholar 

  24. Bjarnason I, Ward K, Peters TJ: The leaky gut of alcoholism: Possible route of entry for toxic compounds. Lancet i:179–182, 1984

    Google Scholar 

  25. Bjarnason I, Levi S, Smethurst P, Menzies IS, Levi AJ: Vindaloo and you. BMJ 297:1629–1631, 1988

    Google Scholar 

  26. Laker MF, Gunn WG: Natural occurrence disqualifies manitol as an internal standard when urinary monosaccharides are determined by gas liquid chromatography. Clin Chim Acta 96:265–267, 1979

    Google Scholar 

  27. Laker MF, Mount JN: Mannitol estimation in biological fluids by gas-liquid chromatography of trimethylsilyl derivatives. Clin Chem 26:441–443, 1980

    Google Scholar 

  28. Blood J, Ingle AR, Allinson N, Davies GR, Hill PG: Rapid enzymatic method for measurement of mannitol in urine. Ann Clin Chem 28:401–406, 1991

    Google Scholar 

  29. Robert A: An intestinal disease produced experimentally by a prostaglandin deficiency. Gastroenterology 69:1045–1047, 1975

    Google Scholar 

  30. Del Soldato P, Foschi D, Benoni G, Scarpignato C: Oxygen free radicals interact with indomethacin to cause gastrointestinal injury. Agents Actions 17:484–488, 1985

    Google Scholar 

  31. Akamatsu H, Oguchi M, Nishijima S, Asada Y, Takahashi M, Ushijima T, Niwa Y: The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: A possible mechanism of action of metronidazole in rosacea and acne. Arch Dermatol Res 282:449–454, 1991

    Google Scholar 

  32. Miyachi Y, Yoshioka A, Imamura S, Niwa Y: Effect of sulphasalazine and its metabolites on the generation of reactive oxygen species. Gut 28:190–195, 1987

    Google Scholar 

  33. Grove DI, Mahmoud AF, Warren KS: Suppression of cell-mediated immunity by metronidazole. Int Arch Allergy Appl Immunol 54:422–427, 1977

    Google Scholar 

  34. Helleberg L: Clinical pharmacokinetics of indomethacin. Clin Pharmacokinet 6:245–258, 1981

    Google Scholar 

  35. Duggan DE, Hooke KF, Noll RM, Kwan KC: Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharmacol 25:1749–1754, 1975

    Google Scholar 

  36. Scoenhard G, Opperman J, Kohn FE: Metabolism of and pharmacokinetic studies of misoprostol. Dig Dis Sci 30:126S-128S, 1985

    Google Scholar 

  37. Steiner JA: Misoprostol clinical pharmacokinetics. Dig Dis Sci 30:136S-141S, 1985

    Google Scholar 

  38. Isselbacher KJ: The role of arachidonic acid metabolites in gastrointestinal homeostasis. Biochemical, histological and clinical effects. Drugs 33 (suppl 1):38–46, 1983

    Google Scholar 

  39. Yamada T, Specian RD, Granger DN, Gaginella TS, Grisham MB: Misoprostol attenuates acetic acid-induced increases in mucosal permeability and inflammation: Role of blood flow. Am J Physiol 261:G332-G339, 1992

    Google Scholar 

  40. Patrono C: Pharmacologic modulation of the cyclooxygenase pathway in the human kidney. Adv Prostaglandin Thromboxane Leukotriene Res 20:250–256, 1990

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gastrointestinal Science Research Unit, The London Hospital Medical College, 26 Ashfield Street, E1 2AJ, London, UK

    Gareth R. Davies MRCP, Martin E. Wilkie MRCP & David S. Rampton FRCP

  2. Department of Renal Medicine, The Royal London Hospital, E1 1BB, London, UK

    Gareth R. Davies MRCP, Martin E. Wilkie MRCP & David S. Rampton FRCP

Authors
  1. Gareth R. Davies MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin E. Wilkie MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David S. Rampton FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Dr. Davies is partly supported by a grant from Searle and Dr. Wilkie by a grant from Bayer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davies, G.R., Wilkie, M.E. & Rampton, D.S. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Digest Dis Sci 38, 417–425 (1993). https://doi.org/10.1007/BF01316493

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01316493

Key Words

Search

Navigation