DEVELOPMENT OF A NOVEL TACROLIMUS PRODRUG TO TARGET THE COLON FOR TREATMENT OF COLITIS

Ulcerative colitis (UC) is a severe autoimmune disease that affects the colon and impacts nearly 700,000 Americans annually. Current treatments including approved pharmaceuticals and colectomies, exhibit severe side effects and are largely ineffective for long term management of the disease. Tacrolimus, a potent immunosuppressant, has been used off label to treat UC, appearing highly efficacious. However a high dosage is currently needed to overcome insufficient delivery to the colon, significantly increasing adverse effects due to systemic circulation. The goal of this research was to use a prodrug strategy for site-specific delivery of tacrolimus to the colon, to create a highly efficacious UC treatment with minimal off target uptake and adverse effects. A synthetic strategy was developed for sulfating tacrolimus to improve solubilization, reducing drug permeability during transport to the site. Sulfatase enzymes expressed by gut microflora were utilized to release the parent drug for site-specific treatment of UC. The permeability of the drug in both its sulfated and non-sulfated states was tested on the Caco-2 model. The results suggest the prodrug strategy was successful, and that sulfated tacrolimus would remain impermeable in the upper GI tract with gut microflora releasing the parent therapeutic agent on site to treat UC.