Abstract
Excretion of orally administrated 51Cr-EDTA as a marker of small intestinal permeability (a proposed prerequisite for human enteropathy) is increased by corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). We have investigated the suitability of the rat as an animal model of small intestinal permeability using orally administered 51Cr-EDTA. We dosed Sprague-Dawley rats with NSAIDs and corticosterone followed by 51Cr-EDTA under conditions reported for humans and measured urinary excretion of the marker. In control rats, the urinary excretion of 51Cr-EDTA exhibited a skewed-to-the-left frequency distribution curve with a median of 2.13% of the dose. No sex-related differences were noticed in the baseline permeability. In male rats, single therapeutically equivalent doses of indomethacin, flurbiprofen, ibuprofen, naproxen, diclofenac, sulindac, nambumetone, and corticosterone, increased the intestinal permeability by different extents with indomethacin eliciting the maximum effect, and the last four drugs showing minimal potencies. Therapeutically relevant doses of aspirin did not have any significant effect. The increase in permeability was dependent upon the NSAIDs dose. Administration of glucose/citrate, misoprostol and sulfasalazine significantly reduced the effect of indomethacin. Misoprostol antagonized the effect of naproxen but H2-antagonists and sucralfate did not. All the above observations made in the rat were similar to those previously reported for humans. Thus the rat is a suitable model for studies of small intestinal permeability.
Similar content being viewed by others
REFERENCES
K. D. Rainsford. Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. Scand. J. Gastroentrol. 24:9–16 (1989).
I. Bjarnason, J. Hayllar, A. J. Macpherson, and A. S. Russell. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine. Gastroenterology 104:1832–1847 (1993).
A. J. Morris, R. Madhok, R. D. Sturrock, H. A. Capell, and J. F. MacKenzie. Enteroscopic diagnosis of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs. Lancet 337:520 (1991).
I. Bjarnason, P. Williams, P. Smethurst, T. J. Peters, and A. J. Levi. Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 27:1292–1297 (1986).
I. Bjarnason, A. So, A. J. Levi, T. J. Peters, D. Williams, G. D. Zanelli, J. M. Gumpel, and B. Ansell. Intestinal permeability and inflammation in rheumatoid arthritis: Effects of non-steroidal anti-inflammatory drugs. Lancet i:1171–1173 (1984).
R. T. Jenkins, R. T. Rooney, D. R. Jones, J. Bienenstock, and R. L. Goodacre. Increased intestinal permeability in patients with rheumatoid arthritis: a side-effect of oral non-steroidal antiinflammatory drug therapy? Br. J. Rheumatol. 26:103–107 (1987).
L. Aabakken, S. Larsen, and M. Osnes. Sucralfate for prevention of naproxen-induced mucosal lesions in the proximal and distal gastrointestinal tract. Scand. J. Rheumatology 18:361–368 (1989).
L. Aabakken. 51Cr-Ethylenediaminetetraacetic acid absorption test: methodological aspects. Scand. J. Gastroenterol. 24:351–358 (1989).
F. L. Lanza, G. L. Royer, R. S. Nelson. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N. Engl. J. Med. 303:(3)136–138 (1980).
K. D. Rainsford. In R. A. Greenwald and H. S. Diamond (eds.), In Handbook of Animal Models for Rheumatic Diseases, CRC Press, Boca Raton, 1988.
I. Bjarnason, P. Smethurst, A. J. Levi, and T. J. Peters. Intestinal permeability to 51Cr-EDTA in rats with experimentally induced enteropathy. Gut 26:579–585 (1985).
J. K. Ramage, R. T. Jenkins, R. H. Hunt, and M. H. Perdue. Permeability of inflamed jejunum to 51Cr-EDTA in the in vivo rat. Gastroenterology A1261 (1988).
H. Mielants, S. Goemaere, M. De Vos, K. Schelstraete, K. Goethal, M. Maertens, C. Ackerman, and E. M. Veys. Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs. J. Rheumatol. 18:389–393 (1991).
I. Bjarnason, P. Smethurst, C. G. Fenn, C. E. Lee, I. S. Menzies, and J. Levi. Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig. Dis. and Sci. 34:407–411 (1989).
G. R. Davies, and D. S. Rampton. The pro-drug sulindac may reduce the risk of intestinal damage associated with the use of conventional non-steroidal anti-inflammatory drugs. Aliment. Pharmacol. Therap. 5:593–598 (1991).
G. R. Davies, M. E. Wilkie, and D. S. Rampton. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig. Dis. and Sci. 38(3):417–425 (1993).
I. Bjarnason, P. Smethurst, A. Macpherson, F. Walker, J. C. McElnay, P. Passmore, and I. S. Menzies. Glucose and citrate reduce the permeability changes caused by indomethacin in humans. Gastroenterology 102:1546–1550 (1992).
A. K. Banerjee, R. Sherwood, J. A. Rennie, and T. J. Peters. Sulphasalazine reduces indomethacin induced changes in small intestinal permeability in man. Brit. Soc. Gast. A 593 (1991).
I. Bjarnason, B. Fehilly, P. Smethurst, I. S. Menzies, and A. J. Levi. Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man. Gut. 32:275–277 (1991).
L. Aabakken, and M. Osnes. 51Cr-Ethylenediaminetetraacetic acid absorption test. Effects of naproxen, a non-steroidal, anti-inflammatory drug. Scand. J. Gastroenterol. 25:917–924 (1990).
R. T. Jenkins, P. J. Rooney, and R. H. Hunt. Increased bowel permeability to [51Cr]EDTA in controls caused by Naproxen is not prevented by cytoprotection. Arthritis. Rheum. 31:(Suppl 1)R11 (1988).
L. Aabakken, S. Larsen, and M. Osnes. Cimetidine tablets or suspension for the prevention of gastrointestinal mucosal lesions caused by non-steroidal, anti-inflammatory drugs. Scand. J. Rheumatology 18:369–375 (1989).
L. Aabakken, B. A. Bjørnbeth, R. Weberg, L. Vikmoen, S. Larsen, and M. Osnes. NSAID-associated gastroduodenal damage does famotidine protection extend into the mid and distal duodenum? Aliment. Pharmacol. Therap. 4:295–303 (1990).
M. Rowland, and S. Riegelman. Pharmacokinetics of acetylsalicylic acid and salicylic acid after iv administration in man. J. Pharm. Sci. 2:1313–1319 (1968).
J. A. Mitchell, P. Akarasereenont, C. Thiemermann, R. J. Flower, and J. R. Vane. Selectivity of non-steroidal antiinflammatory drugs as inhibitors of constitutive an inducible cyclooxygenase. Proc. Natl. Acad. Sci. 90:11693–11697 (1994).
D. W. Powell. Barrier function of epithelia. American Journal of Physiology 266:275–288 (1981).
K. D. Rainsford. Prevention of indomethacin-induced gastrointestinal ulceration in rats by glucose-citrate formulation: Role of ATP in mucosal defenses. Br. J. Rheumatol. 26:(suppl 2):81 (1980).
I. Bjarnason, T. J. Peters, and N. Veall. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labeled EDTA absorption test. Lancet i:323–325 (1993).
L. O. Simpson. NSAIDs and the leaky gut. Lancet i:218 (1985).
I. Bjarnason, G. Zanelli, T. Smith, P. Smethurst, A. B. Price, M. J. Gumpel, and A. J. Levi. The pathogenesis and consequence of non-steroidal anti-inflammatory drug induced small intestinal inflammation. Scand. J. Rheumatol. suppl. 64:55–62 (1987).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Davies, N.M., Wright, M.R. & Jamali, F. Antiinflammatory Drug-Induced Small Intestinal Permeability: The Rat Is a Suitable Model. Pharm Res 11, 1652–1656 (1994). https://doi.org/10.1023/A:1018978308752
Issue Date:
DOI: https://doi.org/10.1023/A:1018978308752