Background/Aims: Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn’s disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis. Materials and Methods: We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres. Results: The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1β (IL-1β), and IL-6, and minimized the histological and morphometric changes. Conclusion: The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

1.
Matsuoka K, Kobayashi T, Ueno F, Matsui T, Hirai F, Inoue N, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018 Mar;53(3):305–53.
2.
Ishige T, Tomomasa T, Takebayashi T, Asakura K, Watanabe M, Suzuki T, et al. Inflammatory bowel disease in children: epidemiological analysis of the nationwide IBD registry in Japan. J Gastroenterol. 2010 Sep;45(9):911–7.
3.
Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008 Oct;135(4):1114–22.
4.
Moss AC, Peppercorn MA. Steroid-refractory severe ulcerative colitis: what are the available treatment options? Drugs. 2008;68(9):1157–67.
5.
Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a systematic review. Inflamm Bowel Dis. 2011 Jan;17(1):440–9.
6.
Turner D, Ruemmele FM, Orlanski-Meyer E, Griffiths AM, de Carpi JM, Bronsky J, et al. Management of Paediatric Ulcerative Colitis, Part 2: Acute Severe Colitis-An Evidence-based Consensus Guideline From the European Crohn’s and Colitis Organization and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018 Aug;67(2):292–310.
7.
Belitsky P, Dunn S, Johnston A, Levy G. Impact of absorption profiling on efficacy and safety of cyclosporin therapy in transplant recipients. Clin Pharmacokinet. 2000 Aug;39(2):117–25.
8.
Kwak CS, Mun KC. The beneficial effect of melatonin for cyclosporine hepatotoxicity in rats. Transplant Proc. 2000 Nov;32(7):2009–10.
9.
Komaki Y, Komaki F, Ido A, Sakuraba A. Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis; A Systematic Review and Meta-analysis. J Crohn’s Colitis. 2016 Apr;10(4):484–94.
10.
Navas-López VM, Blasco Alonso J, Serrano Nieto MJ, Girón Fernández-Crehuet F, Argos Rodriguez MD, Sierra Salinas C. Oral tacrolimus for pediatric steroid-resistant ulcerative colitis. J Crohn’s Colitis. 2014 Jan;8(1):64–9.
11.
Yanagi T, Ushijima K, Koga H, Tomomasa T, Tajiri H, Kunisaki R, et al. Tacrolimus for ulcerative colitis in children: a multicenter survey in Japan. Intest Res. 2019 Oct;17(4):476–85.
12.
Naeem M, Bae J, Oshi MA, Kim MS, Moon HR, Lee BL, et al. Colon-targeted delivery of cyclosporine A using dual-functional Eudragit® FS30D/PLGA nanoparticles ameliorates murine experimental colitis. Int J Nanomedicine. 2018 Feb;13:1225–40.
13.
Dalziel JE, Young W, Bercik P, Spencer NJ, Ryan LJ, Dunstan KE, et al. Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility. Neurogastroenterol Motil. 2016 Aug;28(8):1241–51.
14.
Murthy SN, Cooper HS, Shim H, Shah RS, Ibrahim SA, Sedergran DJ. Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin. Dig Dis Sci. 1993 Sep;38(9):1722–34.
15.
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 Feb;22(2):193–9.
16.
Melero A, Draheim C, Hansen S, Giner E, Carreras JJ, Talens-Visconti R, et al. Targeted delivery of Cyclosporine A by polymeric nanocarriers improves the therapy of inflammatory bowel disease in a relevant mouse model. Eur J Pharm Biopharm. 2017 Oct;119:361–71.
17.
Hashimoto Y, Sasa H, Shimomura M, Inui K. Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Pharm Res. 1998 Oct;15(10):1609–13.
18.
Saitoh H, Saikachi Y, Kobayashi M, Yamaguchi M, Oda M, Yuhki Y, et al. Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine. Eur J Pharm Sci. 2006 May;28(1-2):34–42.
19.
Mitschke D, Reichel A, Fricker G, Moenning U. Characterization of cytochrome P450 protein expression along the entire length of the intestine of male and female rats. Drug Metab Dispos. 2008 Jun;36(6):1039–45.
20.
Mencarelli A, Khameneh HJ, Fric J, Vacca M, El Daker S, Janela B, et al. Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis. Nat Commun. 2018 Mar;9(1):1102.
21.
Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011 May;140(6):1756–67.
22.
Moini M, Schilsky ML, Tichy EM. Review on immunosuppression in liver transplantation. World J Hepatol. 2015 Jun;7(10):1355–68.
23.
Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–42.
24.
Obeidat WM, Price JC. Preparation and evaluation of Eudragit S 100 microspheres as pH-sensitive release preparations for piroxicam and theophylline using the emulsion-solvent evaporation method. J Microencapsul. 2006 Mar;23(2):195–202.
25.
Murad HA, Abdallah HM, Ali SS. Mentha longifolia protects against acetic-acid induced colitis in rats. J Ethnopharmacol. 2016 Aug;190:354–61.
26.
Dodda D, Chhajed R, Mishra J. Protective effect of quercetin against acetic acid induced inflammatory bowel disease (IBD) like symptoms in rats: possible morphological and biochemical alterations. Pharmacol Rep. 2014 Feb;66(1):169–73.
27.
Kirino S, Fukunaga J, Ikegami S, Tsuboi H, Kimata M, Nakata N, et al. Regulation of bone metabolism in immunosuppressant (FK506)-treated rats. J Bone Miner Metab. 2004;22(6):554–60.
28.
Pech T, Fujishiro J, Finger T, von Websky M, Stoffels B, Wehner S, et al. Effects of immunosuppressive therapy after experimental small bowel transplantation in rats. Transpl Immunol. 2011 Sep;25(2-3):112–8.
29.
Badhana S, Garud N, Garud A. Colon specific drug delivery of mesalamine using eudragit S100-coated chitosan microspheres for the treatment of ulcerative colitis. Int Curr Pharm J. 2013;2(3):42–8.
30.
Prasanth V, Jayaprakash R, Mathew ST. Colon Specific Drug Delivery Systems: A Review on Various Pharmaceutical Approaches. 2012.
31.
Watanabe M, Yamazaki M, Kanai T. Mucosal T cells as a target for treatment of IBD. J Gastroenterol. 2003 Mar;38(Suppl 15):48–50.
32.
Dinarello CA. Interleukin-1beta and the autoinflammatory diseases. N Engl J Med. 2009 Jun;360(23):2467–70.
33.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005 Nov;23(5):479–90.
34.
Li Y, de Haar C, Chen M, Deuring J, Gerrits MM, Smits R, et al. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut. 2010 Feb;59(2):227–35.
35.
Sanchez-Muñoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol. 2008 Jul;14(27):4280–8.
36.
Yoshino T, Nakase H, Honzawa Y, Matsumura K, Yamamoto S, Takeda Y, et al. Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis. Inflamm Bowel Dis. 2010 Dec;16(12):2022–33.
37.
Zhu L, Gu P, Shen H. Protective effects of berberine hydrochloride on DSS-induced ulcerative colitis in rats. Int Immunopharmacol. 2019 Mar;68:242–51.
38.
Atreya R, Neurath MF. Current and future targets for mucosal healing in inflammatory bowel disease. Visc Med. 2017 Mar;33(1):82–8.
39.
Miyoshi J, Matsuoka K, Inoue N, Hisamatsu T, Ichikawa R, Yajima T, et al. Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients. J Crohn’s Colitis. 2013 Dec;7(12):e609–14.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.