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Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease

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Abstract

Introduction

Several new derivatives of sulphasalazine that make use of its active moiety, 5-aminosalicylic acid (5-ASA), have been introduced for the treatment of inflammatory bowel disease (IBD). In rats short term intravenous administration of 5-ASA has been associated with nephrotoxicity. A number of cases of nephrotoxicity have been reported recently in IBD patients taking oral maintenance treatment with 5-ASA compounds.

Objective

To study the urinary and serum levels of acetylated 5-ASA (Ac-5-ASA) and the unacetylated 5-ASA (5-ASA) in patients with IBD maintained on sulphasalazine, olsalazine and mesalazine (pH dependent release form). We also sought correlation between levels of 5-ASA, clinical disease activity and extent of disease.

Methods

We studied 79 patients (male, n=30; female, n=49) with established IBD [ulcerative colitis (UC), n=48; Crohn’s disease (CD), n=31], 72 maintained on 5-ASA compounds (sulphasalazine = 27; olsalazine = 28; mesalazine = 17) and 7 patients were receiving no medication. Urinary and serum analysis of 5-ASA was performed by high performance liquid chromatography (HPLC). Clinical disease activity was quantified using simple index of Harvey and Bradshaw.

Results

Patients receiving mesalazine had significantly higher levels of serum free 5-ASA compared to those who were receiving olsalazine and sulphasalazine (mesalazine mean ± SEM; range; 2.84 ±1.21 (0.00–16.00) vs olsalazine 0.45 ±0.18 (0.00–16.20); μmol/L; p< 0.04; sulphasalazine 0.37 ±0.25 (0.00−3.74); p< 0.03). Similarly levels of urinary free 5-ASA were significantly higher in patients maintained on mesalazine compared to those on olsalazine or sulphasalazine (mesalazine 219 ±80.43 (0.00−1050) vs olsalazine 33.3 ± 17.23 (0.00–317) μmol/L; p< 0.01; and sulphasalazine 15 ±8.86 (0.00–192); p< 0.05). However, no significant difference was observed in the levels of urinary free 5-ASA between olsalazine and sulphasalazine. No significant difference was observed in the levels of free-5-ASA in UC patients with left sided disease and those with extensive disease. Furthermore, no significant difference was observed in the levels of serum and urinary 5-ASA in CD patients with ileo-colic disease and colonic disease. Urinary and serum free-5-ASA did not correlate with the clinical disease activity.

Conclusion

Systemic absorption of 5-ASA from sulphasalazine and olsalazine is relatively low. However, pH-dependent mesalazine formulations may release their contents rapidly in the small intestine and proximal colon resulting in higher plasma and urinary concentrations of free.5-ASA. The effects of free 5-ASA on renal function in the human require further evaluation.

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References

  1. Taffet, S. L., Das, K. M. Sulphasalazine: adverse effects and desensitization. Dig. Dis. Sci. 1983; 28: 833–42.

    Article  PubMed  CAS  Google Scholar 

  2. Azad Khan, A. K., Piris, J., Truelove, S. C. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977; i: 892–5.

    Article  Google Scholar 

  3. Dissanayake, A. S., Truelove, S. C. A controlled therapeutic trial of long term maintenance treatment of ulcerative colitis with sulphasalazine. Gut 1973; 14: 923–6.

    Article  PubMed  CAS  Google Scholar 

  4. Myers, B., Evan, D. N. W., Rhode, J. et al. Metabolism and urinary excretion of 5-aminosalicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in gastrointestinal tract. Gut 1987; 28: 196–200.

    Article  PubMed  CAS  Google Scholar 

  5. Sandberg-Green II, Ryde, M., Jarnerot, G. Absorption and excretion of a single 1-g dose of asodiasal sodium in subjects with ileostomy. Scand. J. Gastroenterol. 1983; 18: 107–11.

    Article  Google Scholar 

  6. Willoughby, C. P., Aronsson, J. K., Agback, H., Bodin, N. O., Truelove, S. C. Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis. Gut 1982; 23: 1081–7.

    Article  PubMed  CAS  Google Scholar 

  7. Dew, M. J., Hughes, P. J., Lee, M. G., Evans, B. K. Rhodes, J. An oral preparation to release drugs in the human colon. Br. J. Clin. Pharmacol. 1982; 14: 405–8.

    PubMed  CAS  Google Scholar 

  8. Dew, M. J., Ryder, E. E. J., Evan N., Evans, B. K., Rhodes, J. Colonic release of 5-ASA from an oral preparation in active ulcerative colitis. Br. J. Clin. Pharmacol. 1983; 15: 185–7.

    Google Scholar 

  9. Calder, I. C., Funder, C. C., Green, C. R., Ham, K. N., Tange, J. D. Nephrotoxic lesion from 5-aminosalicylic acid. BMJ 1972; i: 52–4.

    Google Scholar 

  10. Masson, E. A., Rhodes, J. M. Mesalazine associated. nephrogenic diabetes isipidus presenting as weight loss. Gut 1992; 33: 563–564.

    Article  PubMed  CAS  Google Scholar 

  11. Barbour, V. M., Williams, P. F. Nephrotic syndrome associated with sulphasalazine. BMJ 1990; 310: 818.

    Article  Google Scholar 

  12. Novis, B. H., Korzets, Z., Chen, P., Bernheim, J. Nephrotic syndrome after treatment with 5-aminosalicylic acid. BMJ 1988; 296: 1442.

    PubMed  CAS  Google Scholar 

  13. Harvey, R. F., Bradshaw, J. W. A simple index of Crohn’s disease activity. Lancet 1980; i: 514.

    Article  Google Scholar 

  14. Ryde, M., Ahnfelt, N-O. The pharmacokinetics of olsalazine sodium in healthy volunteers after a single iv dose and after oral doses with and without food. Eur. J. Clin. Pharmacol. 1988; 34: 481–8.

    Article  PubMed  CAS  Google Scholar 

  15. De Vos, M., Verdievel, H., Schoonjans, R., Beke, R., De Weerdt, G. A., Barbier, F. High performance liquid Chromatographic assay for the determination of 5- aminosalicylic acid and acetyl-5-aminosalicylic acid concentrations in endoscopic intestinal biopsy in humans. J. Chromatogr. 1991; 564: 296–302.

    Article  PubMed  Google Scholar 

  16. Backman, L., Appelkvist, E. L., Ringden, O., Dallner, G. Glutathione transferase in the urine: a marker for post transplantation tubular lesion. Kidney Int. 1988; 33: 571–7.

    Article  PubMed  CAS  Google Scholar 

  17. Bilyard, K. G., Joseph, E. C., Metcalf, R. Mesalazine: an overview of key pre-clinical studies, Scand. J. Gastroenterology 1990: 25 (suppl): 52–5.

    Article  Google Scholar 

  18. Mathew, H., Lawson, A. A. H. Acute poisoning o due to salicylate, phenacetin and paracetamol. In: Mathew, H., Lawson, A. A. H., eds. Treatment of common acute poisonings, 4th ed. Edinburgh: Churchill Livingstone, 1979: 82–93.

    Google Scholar 

  19. Henning, H. V., Meinhold, J., Eisenhauer, T., Scheler, F. Chronische intersititielle nephritis nach Behandlung mit 5- aminosalicylause. Dtsch. Med. Wochenschr. 1989; 114; (27): 1091.

    PubMed  CAS  Google Scholar 

  20. Thuluvath, P. J., Ninkovic, M., Calam, J., Anderson, M. Mesalazine induced interstitial nephritis. Gut 1990; 35: 1493–1496.

    Article  Google Scholar 

  21. Lockwood, T. D., Bosmann, H. B. The use of urinary N- acetylglucosaminidase in human renal toxicology II. elevation of human excretion after aspirin and sodium salicylate. Toxicol. Appl. Pharmacol. 1979; 49: 337–45.

    Article  PubMed  CAS  Google Scholar 

  22. Proctor, R. A., Kunin, C.M. Salicylate induced enzymuria. Am. J. Med. 1978: 65: 987–93.

    Article  PubMed  CAS  Google Scholar 

  23. Brander, L., Kuhlback, B., Niemiste, M., Riska, N. The effect of massive doses of PAS on renal function and electrolyte balance. Scand. J. Clin. Med. 1963; 15: 38.

    CAS  Google Scholar 

  24. Riley, S. A., Mani, V., Goodman, M. J., Herd, M. E., Dutt, S., Turnberg, L. A. Comparison of delayed release 5- aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse. Gut 1988; 29: 669–74.

    Article  PubMed  CAS  Google Scholar 

  25. Schreiber, S., Hamling, J., Zehnter, W., Howaldt, S., Daerr, W. H., Raedler, A., Kruis, W. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut 1997; 40: 761–766.

    Article  PubMed  CAS  Google Scholar 

  26. von Muhlendahl, K. E. Nephritis durch 5- aminosalicylsaure. Dtsch. Med. Wochestchr. 1989; 114: 236.

    Google Scholar 

  27. Laursen, L. S., Stokholm, M., Bukhave, K., Rask-Madsen, J., Lauritsen, K. Disposition of 5-ASA by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion. Gut 1990; 31: 1271–76.

    Article  Google Scholar 

  28. Evans, D. F., Pye, G., Bramley, R., Clark, A. G., Dyson, T. J., Hardcastle, J. D. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988; 29: 1035–1041.

    Article  PubMed  CAS  Google Scholar 

  29. Raimundo, A. H., Evans, D. F., Rogers, J., Jameson, J., Silk, D. B. A. Intestinal pH in ulcerative colitis: Acute (untreated) and in remission on 5-aminosalicylic. Gut 1992; 33(No 1): S63.

    Google Scholar 

  30. Hayllar, J., Bjamason, I. Sulphasalazine in ulcerative colitis; In memorium? Gut 1991; 32: 462–3.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Republic of Ireland

    N. Mahmud, D. G. Weir & D. Kelleher

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  1. N. Mahmud
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  2. D. G. Weir
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Mahmud, N., Weir, D.G. & Kelleher, D. Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease. Ir. J. Med. Sc. 168, 228–232 (1999). https://doi.org/10.1007/BF02944345

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