Colon-Specific Delivery of Febuxostat via an Amino Acid Conjugate Enhances Anti-Colitis Efficacy and Limits Systemic Exposure.

Background/objectives: Febuxostat (FBXT), a xanthine oxidase (XO) inhibitor, is a urate-lowering drug commonly used to treat gout. XO is also a promising therapeutic target for inflammatory bowel disease (IBD). This study aimed to improve the efficacy and safety of FBXT repurposed for the treatment of IBD.

Methods

FBXT was conjugated with the acidic amino acids aspartic acid (Asp) and glutamic acid (Glu) via amide linkages to yield the colon-specific conjugates FBXT-Asp and FBXT-Glu.

Results

The results revealed that amino acid conjugation decreased the distribution coefficient of FBXT from 1.451 to -1.217 for FBXT-Asp and -0.859 for FBXT-Glu. In parallel, conjugation retarded FBXT transport across the small intestinal wall, with a more pronounced effect observed with Glu conjugation than with Asp conjugation. The conjugates were converted to FBXT in cecal contents under a nitrogen atmosphere while remaining intact in pH 1.2 buffer and small intestinal contents. The cecal conversion percentages at 8 and 24 h were 7.1% and 22%, respectively, for FBXT-Asp and 17% and 54.8%, respectively, for FBXT-Glu. Consistent with these in vitro results, oral gavage of FBXT-Glu resulted in greater FBXT accumulation in the rat cecum than that observed with free FBXT. In rats with 2,4-dinitrobenzenesulfonic acid-induced colitis, oral gavage of FBXT-Glu at a dose equivalent to 20 mg of FBXT ameliorated colonic damage and inflammation. This effect was more potent than that of FBXT at the same dose or sulfasalazine (SSZ), a currently used anti-IBD drug. Additionally, FBXT-Glu did not produce detectable blood levels of FBXT, whereas FBXT was detected at concentrations of up to 6.7 μM at 2 h after oral gavage of FBXT at the corresponding dose.

Conclusions

FBXT-Glu may serve as an anti-colitis agent with therapeutic and toxicological advantages over FBXT and could be a viable alternative to SSZ.