FK506 microparticles mitigate experimental colitis with minor renal calcineurin suppression

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.

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.

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.

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.