Skip to main content
SpringerLink
Log in

Tacrolimus, Sirolimus, and Mycophenolate Mofetil

  • Chapter
  • First Online:
Medical Therapy of Ulcerative Colitis

Abstract

Cyclosporine was introduced as rescue therapy for corticosteroid-refractory ulcerative colitis in the early 1990s. However, the safety profile of cyclosporine, especially in the long run, appears rather unfavorable. Neurological side effects such as paresthesias, nephrotoxicity, hypertension, headache, and gingival hyperplasia have been reported in up to one third of patients. As a consequence, an intense search for novel calcineurin inhibitors commenced which led to the isolation of a macrolide produced by Streptomyces tsukubaensis that was later termed tacrolimus. Similar to cyclosporine, tacrolimus acts by inhibiting calcineurin, a phosphatase required for the translocation of the transcription factor nuclear factor of activated T cells into the nucleus, where it controls production of interleukin-2 in T lymphocytes. Sirolimus, another macrolide, was originally named rapamycin after its isolation from a soil sample derived from Easter Island. It is produced by Streptomyces hygroscopicus and was initially characterized as a powerful antifungal compound. Further analyses, however, revealed its potent cytostatic and immunosuppressive activities, and as a result, sirolimus and its derivative everolimus are currently being used or evaluated for the treatment of a variety of pathological conditions including certain cancers, graft-versus-host disease, and polycystic kidney disease. Although sirolimus resembles tacrolimus structurally and binds to the same intracellular target FKBP12, its mode of action does not involve inhibition of calcineurin signaling. Instead, the sirolimus-FKBP12 complex inhibits a serine/threonine kinase termed mTOR (for mammalian target of rapamycin) that is of pivotal importance for a variety of key developmental and cell biological functions.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330:1841–5.

    Article  CAS  PubMed  Google Scholar 

  2. Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet. 1990;336:16–9.

    Article  CAS  PubMed  Google Scholar 

  3. Naganuma M, Fujii T, Watanabe M. The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease. J Gastroenterol. 2011;46:129–37.

    Article  CAS  PubMed  Google Scholar 

  4. Laharie D, Bourreille A, Branchè J, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 2012;380:1909–15.

    Article  CAS  PubMed  Google Scholar 

  5. Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987;40:1249–55.

    Article  CAS  Google Scholar 

  6. Thomson AW, Carroll PB, McCauley J, et al. FK 506: a novel immunosuppressant for treatment of autoimmune disease. Rationale and preliminary clinical experience at the University of Pittsburgh. Springer Semin Immunopathol. 1993;14:323–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Sigal NH, Dumont FJ. Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519–60.

    Article  CAS  PubMed  Google Scholar 

  8. Aiko S, Conner EM, Fuseler JA, Grisham MB. Effects of cyclosporine or FK506 in chronic colitis. J Pharmacol Exp Ther. 1997;280:1075–84.

    CAS  PubMed  Google Scholar 

  9. Hoshino H, Goto H, Sugiyama S, Hayakawa T, Ozawa T. Effects of FK506 on an experimental model of colitis in rats. Aliment Pharmacol Ther. 1995;9:301–7.

    Article  CAS  PubMed  Google Scholar 

  10. Higa A, McKnight GW, Wallace JL. Attenuation of epithelial injury in acute experimental colitis by immunomodulators. Eur J Pharmacol. 1993;239:171–6.

    Article  CAS  PubMed  Google Scholar 

  11. Takizawa H, Shintani N, Natsui M, et al. Activated immunocompetent cells in rat colitis mucosa induced by dextran sulfate sodium and not complete but partial suppression of colitis by FK506. Digestion. 1995;56:259–64.

    Article  CAS  PubMed  Google Scholar 

  12. Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol. 1998;93:1860–6.

    Article  CAS  PubMed  Google Scholar 

  13. Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease—a long-term follow-up. Am J Gastroenterol. 2006;101:1048–56.

    Article  CAS  PubMed  Google Scholar 

  14. Baumgart DC, Wiedenmann B, Dignass AU. Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease. Aliment Pharmacol Ther. 2003;17:1273–81.

    Article  CAS  PubMed  Google Scholar 

  15. Högenauer C, Wenzl HH, Hinterleitner TA, Petritsch W. Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. Aliment Pharmacol Ther. 2003;18:415–23.

    Article  PubMed  Google Scholar 

  16. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55:1255–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Baumgart DC, Macdonald JK, Feagan B. Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis. Cochrane Database Syst Rev. 2008;CD007216.

    Google Scholar 

  18. Annunziata ML, Hanauer SB. Calcineurin inhibition in severe ulcerative colitis: lost in translation? Inflamm Bowel Dis. 2012;18:809–11.

    Article  PubMed  Google Scholar 

  19. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation. 1997;64:436–43.

    Article  CAS  PubMed  Google Scholar 

  20. McSharry K, Dalzell AM, Leiper K, El-Matary W. Systematic review: the role of tacrolimus in the management of Crohn’s disease. Aliment Pharmacol Ther. 2011;34:1282–94.

    Article  CAS  PubMed  Google Scholar 

  21. Schmidt KJ, Herrlinger KR, Emmrich J, et al. Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis—experience in 130 patients. Aliment Pharmacol Ther. 2013;37:129–36.

    Article  CAS  PubMed  Google Scholar 

  22. Dignass A, Preiss JC, Aust DE, et al. Updated German guideline on diagnosis and treatment of ulcerative colitis, 2011. Z Gastroenterol. 2011;49:1276–341.

    Article  CAS  PubMed  Google Scholar 

  23. Dignass A, Lindsay JO, Sturm A, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis. 2012;6:991–1030.

    Article  PubMed  Google Scholar 

  24. Romano C, Comito D, Famiani A, Fries W. Oral tacrolimus (FK 506) in refractory paediatric ulcerative colitis. Aliment Pharmacol Ther. 2010;31:676–7.

    Article  CAS  PubMed  Google Scholar 

  25. Chow DK, Leong RW. The use of tacrolimus in the treatment of inflammatory bowel disease. Expert Opin Drug Saf. 2007;6:479–85.

    Article  CAS  PubMed  Google Scholar 

  26. Lawrance IC, Copeland TS. Rectal tacrolimus in the treatment of resistant ulcerative proctitis. Aliment Pharmacol Ther. 2008;28:1214–20.

    Article  CAS  PubMed  Google Scholar 

  27. van Dieren JM, van Bodegraven AA, Kuipers EJ, et al. Local application of tacrolimus in distal colitis: feasible and safe. Inflamm Bowel Dis. 2009;15:193–8.

    Article  PubMed  Google Scholar 

  28. Lamprecht A, Schafer U, Lehr CM. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res. 2001;18:788–93.

    Article  CAS  PubMed  Google Scholar 

  29. Lamprecht A, Yamamoto H, Takeuchi H, Kawashima Y. Nanoparticles enhance therapeutic efficiency by selectively increased local drug dose in experimental colitis in rats. J Pharmacol Exp Ther. 2005;315:196–202.

    Article  CAS  PubMed  Google Scholar 

  30. Lamprecht A, Yamamoto H, Takeuchi H, Kawashima Y. A pH-sensitive microsphere system for the colon delivery of tacrolimus containing nanoparticles. J Control Release. 2005;104:337–46.

    Article  CAS  PubMed  Google Scholar 

  31. Lamprecht A, Yamamoto H, Ubrich N, Takeuchi H, Maincent P, Kawashima Y. FK506 microparticles mitigate experimental colitis with minor renal calcineurin suppression. Pharm Res. 2005;22:193–9.

    Article  CAS  PubMed  Google Scholar 

  32. Fellermann K, Tanko Z, Herrlinger KR, et al. Response of refractory colitis to intravenous or oral tacrolimus (FK506). Inflamm Bowel Dis. 2002;8:317–24.

    Article  PubMed  Google Scholar 

  33. Yamamoto S, Nakase H, Mikami S, et al. Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis. Aliment Pharmacol Ther. 2008;28:589–97.

    Article  CAS  PubMed  Google Scholar 

  34. Yamamoto S, Nakase H, Matsuura M, Masuda S, Inui K, Chiba T. Tacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitis. J Clin Gastroenterol. 2011;45:526–30.

    Article  CAS  PubMed  Google Scholar 

  35. Miyoshi J, Matsuoka K, Inoue N, Hisamatsu T, Ichikawa R, Yajima T, Okamoto S, Naganuma M, Sato T, Kanai T, Ogata H, Iwao Y, Hibi T. Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients. J Crohns Colitis. 2013;7(12):e609–14. doi:10.1016/j.crohns.2013.04.018. Epub 2013 May 14.

  36. Bhorade S, Ahya VN, Baz MA, et al. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. Am J Respir Crit Care Med. 2011;183:379–87.

    Article  CAS  PubMed  Google Scholar 

  37. Escher M, Stange EF, Herrlinger KR. Two cases of fatal Pneumocystis jirovecii pneumonia as a complication of tacrolimus therapy in ulcerative colitis—a need for prophylaxis. J Crohns Colitis. 2010;4:606–9.

    Article  CAS  PubMed  Google Scholar 

  38. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo). 1975;28:727–32.

    Article  CAS  Google Scholar 

  39. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975;28:721–6.

    Article  CAS  Google Scholar 

  40. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.

    Article  CAS  PubMed  Google Scholar 

  41. Armand P, Gannamaneni S, Kim HT, et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol. 2008;26:5767–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010;363:830–40.

    Article  CAS  PubMed  Google Scholar 

  43. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.

    Article  CAS  PubMed  Google Scholar 

  44. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009;9:324–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 2011;8:528–39.

    Article  CAS  PubMed  Google Scholar 

  46. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Farkas S, Hornung M, Sattler C, et al. Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis. Int J Colorectal Dis. 2006;21:747–53.

    Article  PubMed  Google Scholar 

  48. Bhonde MR, Gupte RD, Dadarkar SD, et al. A novel mTOR inhibitor is efficacious in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1237–45.

    Article  CAS  PubMed  Google Scholar 

  49. Matsuda C, Ito T, Song J, et al. Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis. Clin Exp Immunol. 2007;148:348–59.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Massey DC, Bredin F, Parkes M. Use of sirolimus (rapamycin) to treat refractory Crohn’s disease. Gut. 2008;57:1294–6.

    Article  CAS  PubMed  Google Scholar 

  51. Dumortier J, Lapalus MG, Guillaud O, et al. Everolimus for refractory Crohn’s disease: a case report. Inflamm Bowel Dis. 2008;14:874–7.

    Article  PubMed  Google Scholar 

  52. Reinisch W, Panes J, Lemann M, et al. A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn’s disease. Am J Gastroenterol. 2008;103:2284–92.

    Article  CAS  PubMed  Google Scholar 

  53. Florey H, Jennings M. Mycophenolic acid; an antibiotic from Penicillium brevicompactum Dlerckx. Lancet. 1946;1:46–9.

    Article  CAS  PubMed  Google Scholar 

  54. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.

    Article  CAS  PubMed  Google Scholar 

  55. Lipsky JJ. Mycophenolate mofetil. Lancet. 1996;348:1357–9.

    Article  CAS  PubMed  Google Scholar 

  56. Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer zum Buschenfelde KH, Schlaak JF. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn‘s disease. Gut. 1999;44:625–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Fellermann K, Steffen M, Stein J, et al. Mycophenolate mofetil: lack of efficacy in chronic active inflammatory bowel disease. Aliment Pharmacol Ther. 2000;14:171–6.

    Article  CAS  PubMed  Google Scholar 

  58. Hassard PV, Vasiliauskas EA, Kam LY, Targan SR, Abreu MT. Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn’s disease. Inflamm Bowel Dis. 2000;6:16–20.

    Article  CAS  PubMed  Google Scholar 

  59. Rampton DS, Neurath MF, Almer S, D’Haens G, Petritsch W, Stange EF. Mycophenolate mofetil in Crohn’s disease. Lancet. 2000;356:163–4.

    Article  CAS  PubMed  Google Scholar 

  60. Orth T, Peters M, Schlaak JF, et al. Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study. Am J Gastroenterol. 2000;95:1201–7.

    Article  CAS  PubMed  Google Scholar 

  61. Palaniappan S, Ford AC, Greer D, et al. Mycophenolate mofetil therapy for refractory inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:1488–92.

    Article  CAS  PubMed  Google Scholar 

  62. Golconda MS, Valente JF, Bejarano P, Gilinsky N, First MR. Mycophenolate mofetil-induced colonic ulceration in renal transplant recipients. Transplant Proc. 1999;31:272–3.

    Article  CAS  PubMed  Google Scholar 

  63. Dalle IJ, Maes BD, Geboes KP, Lemahieu W, Geboes K. Crohn’s-like changes in the colon due to mycophenolate? Colorectal Dis. 2005;7:27–34.

    Article  CAS  PubMed  Google Scholar 

  64. Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea. Transplantation. 2003;75:665–72.

    Article  CAS  PubMed  Google Scholar 

  65. Papadimitriou JC, Cangro CB, Lustberg A, et al. Histologic features of mycophenolate mofetil-related colitis: a graft-versus-host disease-like pattern. Int J Surg Pathol. 2003;11:295–302.

    Article  PubMed  Google Scholar 

  66. Lee S, de Boer WB, Subramaniam K, Kumarasinghe MP. Pointers and pitfalls of mycophenolate-associated colitis. J Clin Pathol. 2012;66(1):8–11.

    Article  CAS  PubMed  Google Scholar 

  67. Skelly MM, Logan RF, Jenkins D, Mahida YR, Hawkey CJ. Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2002;8:93–7.

    Article  PubMed  Google Scholar 

  68. Mathew TH. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation. 1998;65:1450–4.

    Article  CAS  PubMed  Google Scholar 

  69. Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A. 2012;158A:588–96.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology and Hepatology Charité Medical Center - Virchow Hospital Medical School of the Humboldt- University of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Andreas Fischer M.D. & Daniel C. Baumgart M.D., Ph.D.

Authors
  1. Andreas Fischer M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel C. Baumgart M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel C. Baumgart M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Gastroenterology Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Gary R. Lichtenstein

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Fischer, A., Baumgart, D.C. (2014). Tacrolimus, Sirolimus, and Mycophenolate Mofetil. In: Lichtenstein, G. (eds) Medical Therapy of Ulcerative Colitis. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1677-1_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1677-1_14

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-1676-4

  • Online ISBN: 978-1-4939-1677-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation