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Purpose.
FK506 microparticles providing selective colonic drug delivery were tested for their efficiency in a local treatment to the inflamed gut tissue in inflammatory bowel disease (IBD). Because FK506 proved its distinct mitigating potential in the treatment of IBD, risking, however, severe adverse effects, a more selective delivery to the site of inflammation may further improve efficiency and tolerability.
Methods.
A model colitis was induced to male Wistar rats by trinitrobenzenesulfonic acid. FK506 was entrapped into microspheres (MS) prepared with the pH-sensitive polymer Eudragit P-4135F in order to allow drug delivery to the colon. Clinical activity score, colon/body weight index, and myeloperoxidase activity were determined to assess the inflammation, and adverse effects of FK506 resulting from its systemic absorption were quantified as well.
Results.
The clinical activity score and myeloperoxidase activity decreased after the administration of all FK506-containing formulations. The MS formulations proved to be as efficient in mitigating the experimental colitis as the subcutaneous drug solution (myeloperoxidase activity, MS: 9.64 ± 6.6 U/mg tissue; subcutaneous: 7.48 ± 6.96 U/mg) and to be superior to drug solution given by oral route (oral: 12.66 ± 5.46 U/mg; untreated colitis control: 21.88 ± 4.12 U/mg). The FK506 subcutaneous group exhibited increased levels of adverse effects, whereas the FK506-MS group proved its potential to retain the drug from systemic absorption as evidenced by reduced nephrotoxicity.
Conclusions.
The development of this selective delivery system for FK506 should be given particular consideration in the treatment of IBD, as it allows therapy that profits from FK506’s high immune suppressive effect with a simultaneously reduced nephrotoxicity.
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Abbreviations
- IBD:
-
inflammatory bowel disease
- MS:
-
microspheres
References
1. D. R. Friend. Review article: issues in oral administration of locally acting glucocorticosteroids for treatment of inflammatory bowel disease. Aliment. Pharmacol. Ther. 12:591–603 (1998).
2. M. Robinson. Medical therapy of inflammatory bowel disease for the 21st century. Eur. J. Surg. Suppl. 582:90–98 (1998).
3. A. G. Fraser, T. R. Orchard, and D. P. Jewell. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 50:485–489 (2002).
4. O. H. Nielsen, B. Vainer, and J. Rask-Madsen. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment. Pharmacol. Ther. 15:1699–1708 (2001).
5. F. Baert, M. Noman, S. Vermeire, G. Van Assche, G. D’Haens, A. Carbonez, and P. Rutgeerts. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N. Engl. J. Med. 348:601–608 (2003).
6. N. Matsuhashi, A. Nakajima, K. Watanabe, Y. Komeno, A. Suzuki, S. Ohnishi, M. Omata, K. Kondo, Y. Usui, J. I. Iwadare, T. Watanabe, H. Nagawa, and T. Muto. Tacrolimus in corticoid-resistant ulcerative colitis. J. Gastroenterol. 35:655–657 (2000).
7. K. Fellermann, D. Ludwig, M. Stahl, T. David-Walek, and E. F. Stange. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am. J. Gastroenterol. 93:1860–1866 (1998).
8. M. E. Cardenas, D. Zhu, and J. Heitman. Molecular mechanisms of immunosuppression by cyclosporine, FK506, and rapamycin. Curr. Opin. Nephrol. Hypertens. 4:472–477 (1995).
9. T. Wang, B. Y. Li, P. D. Danielson, P. C. Shah, S. Rockwell, R. J. Lechleider, J. Martin, T. Manganaro, and P. K. Donahoe. The immunophilin FKBP12 functions as a common inhibitor of the TGF beta family type I receptors. Cell 86:435–444 (1996).
10. Q. Su, L. Weber, M. Le Hir, G. Zenke, and B. Ryffel. Nephro-toxicity of cyclosporin A and FK506: inhibition of calcineurin phosphatase. Ren. Physiol. Biochem. 18:128–139 (1995).
11. W. F. Finn. FK506 nephrotoxicity. Ren. Fail. 21:319–329 (1999).
12. D. R. Friend. Colon-specific drug delivery. Adv. Drug Del. Rev. 7:149–199 (1991).
13. A. Rubinstein. Approaches and opportunities in colon-specific drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 12:101–149 (1995).
14. P. J. Watts, L. Barrow, K. P. Steed, C. G. Wilson, R. C. Spiller, C. D. Melia, and M. C. Davies. The transit rate of different-sized model dosage forms through the human colon and the effects of a lactulose-induced catharsis. Int. J. Pharm. 87:215–221 (1992).
15. F. H. Hardy, S. S. Davis, R. Khosla, and C. S. Robertson. Gastrointestinal transit of small tablets in patients with ulcerative colitis. Int. J. Pharm. 48:79–82 (1988).
16. H. Nakase, K. Okazaki, Y. Tabata, S. Uose, M. Ohana, K. Uchida, Y. Matsushima, C. Kawanami, C. Oshima, Y. Ikada, and T. Chiba. Development of an oral drug delivery system targeting immune-regulating cells in experimental inflammatory bowel disease: a new therapeutic strategy. J. Pharmacol. Exp. Ther. 292:15–21 (2000).
17. A. Lamprecht, N. Ubrich, H. Yamamoto, U. Schafer, H. Takeuchi, P. Maincent, Y., Kawashima Y, and C.M. Lehr, Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease. J. Pharmacol. Exp. Ther. 299:775–781 (2001).
18. Z. Hu, T. Shimokawa, T. Ohno, G. Kimura, S. S. Mawatari, M. Kamitsuna, Y. Yoshikawa, S. Masuda, and K. Takada. Characterization of norfloxacine release from tablet coated with a new pH-sensitive polymer, P-4135F. J. Drug Target. 7:223–232 (1999).
19. Y. I. Jeong, Y. R. Prasad, T. Ohno, Y. Yoshikawa, N. Shibata, S. Kato, K. Takeuchi, and K. Takada. Application of Eudragit P-4135F for the delivery of ellagic acid to the rat lower small intestine. J. Pharm. Pharmacol. 53:1079–1085 (2001).
20. A. Lamprecht, H. Yamamoto, H. Takeuchi, and Y. Kawashima. Design of pH-sensitive microspheres for the colon delivery of FK506. Eur. J. Pharm. Biopharm. 58:37–43 (2004).
21. G. Hartmann, C. Bidlingmaier, B. Siegmund, S. Albrich, J. Schulze, K. Tschoep, A. Eigler, H. A. Lehr, and S. Endres. Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice. J. Pharmacol. Exp. Ther. 292:22–30 (2000).
22. R. González, S. Rodríguez, C. Romay, O. Ancheta, A. González, J. Armesto, D. Remirez, and N. Merino. Anti-inflammatory activity of phycocyanin extract in acetic acid-induced colitis in rats. Pharmacol. Res. 39:55–59 (1999).
23. J. E. Krawisz, P. Sharon, and W. F. Stenson. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Gastroenterology 87:1344–1350 (1984).
24. A. Higa, G. W. McKnight, and J. L. Wallace. Attenuation of epithelial injury in acute experimental colitis by immunomodulators. Eur. J. Pharmacol. 239:171–176 (1993).
25. H. Hoshino, H. Goto, S. Sugiyama, T. Hayakawa, and T. Ozawa. Effects of FK506 on an experimental model of colitis in rats. Aliment. Pharmacol. Ther. 9:301–307 (1995).
26. S. Aiko, E. M. Conner, J. A. Fuseler, and M. B. Grisham. Effects of cyclosporine or FK506 in chronic colitis. J. Pharmacol. Exp. Ther. 280:1075–1084 (1997).
27. A. Kagayama, S. Tanimoto, J. Fujisaki, A. Kaibara, K. Ohara, K. Iwasaki, Y. Hirano, and T. Hata. Oral absorption of FK506 in rats. Pharm. Res. 10:1446–1450 (1993).
28. Y. Hashimoto, H. Sasa, M. Shimomura, and K. Inui. Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Pharm. Res. 15:1609–1613 (1998).
29. H. Sako, H. Nakashima, T. Sawada, and M. Fukui. Relationship between gelation rate of controlled-release acetaminophen tablets containing polyethylene oxide and colonic drug release in dogs. Pharm. Res. 13:594–598 (1996).
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Lamprecht, A., Yamamoto, H., Ubrich, N. et al. FK506 Microparticles Mitigate Experimental Colitis with Minor Renal Calcineurin Suppression. Pharm Res 22, 193–199 (2005). https://doi.org/10.1007/s11095-004-1186-2
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DOI: https://doi.org/10.1007/s11095-004-1186-2