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Targeted Delivery of Potent Immunosuppressants for Treatment of Ulcerative Colitis
Kleindl, Peter
Kleindl, Peter
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Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) in which inflammation and ulceration are localized to the large intestine. The etiology of UC is unknown, however evidence suggests that the disease is largely autoimmune in nature. Current treatment strategies include aminosalicylates, corticosteroids, immunomodulators and anti-TNF-alpha therapies. Patients often become refractory toward these treatment options over time. Recently, potent macrolide immunosuppressants such as tacrolimus, sirolimus and everolimus have been used off-label to effectively treat UC in otherwise refractory patient populations. Unfortunately, several limitations such as toxicity, interpatient variability and systemic immunosuppression complicates long term use and widespread application. These limitations can potentially be mitigated by improving their delivery to the large intestine after oral dosing. A prodrug strategy can decrease systemic immunosuppressant exposure while simultaneously providing a mechanism to release parent drug via enzymes expressed by bacterial populations within the large intestine. This research focuses on synthesizing sulfate prodrug forms of tacrolimus, sirolimus and everolimus; testing their delivery to the large intestine and propensity for enzymatic release. Parent and prodrug stability was assessed in a variety of physiologically relevant solutions, including biological buffers, simulated and extracted gastrointestinal contents. In vitro intestinal permeability studies and preliminary pharmacokinetic studies were used to assess drug permeability in the small intestine. Enzymatic release of parent drug by bacterial sulfatase was probed using in vitro, in vivo and in silico techniques. Sulfation of the macrolide immunosuppressants of interest improved their delivery to the large intestine and limited systemic exposure after oral dosing. Enzymatic release of parent drug within the colon was not observed, possibly due to incompatibility with the targeted enzymes, limiting treatment efficacy toward UC.
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2020-12-31
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University of Kansas
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Keywords
Pharmaceutical sciences, Drug Delivery, Everolimus, Prodrug, Sirolimus, Tacrolimus, Ulcerative Colitis