Background: Recent immunologic data implicates involvement of mucosal immune cells of
the intestine like eosinophils and mast cells to be functionally involved in the pathogenesis of UC.
Mast cell activation is followed by increased secretion and elevated tissue concentration of histamine.
Inhibition of mucosal histamine release in colon may be an effective therapeutic approach to treat UC.
Some studies report that intestinal inflammation associated with acute and chronic colitis has been
ameliorated by fexofenadine in mice.
Objective: In the present work, we investigated the effect of colon- specific prodrugs of antihistaminic
fexofenadine on TNBS- induced colitis in Wistar rats, applying the principle of drug repositioning.
Method: Amino acid- appended amide prodrugs of fexofenadine were designed and characterized
spectrally. In vitro kinetics and protective effect of prodrugs were studied on TNBS-induced colitis in
Results: Conjugation with amino acids improved the hydrophilicity of fexofenadine (log P: 0.037 to
0.082) to enable efficient delivery to colon. Prodrugs were chemically and enzymatically stable in
aqueous buffers (pH 1.2 and7.4) and stomach homogenates/intestinal homogenates, respectively. Prodrugs
were substantially cleaved to release 60-70% of fexofenadine in homogenates of colon in 12 h.
Prodrug of fexofenadine with L-glutamine additively and significantly suppressed TNBS-induced colitis
showing comparable effects to orally administered 5-aminosalicylic acid.
Conclusion: The outcome of this preliminary work emphasizes involvement of mast cells that release
histamine as one of the important pathological inducers of UC. These promising, dual acting, colontargeting
fexofenadine prodrugs could be explored further for repositioning fexofenadine in the treatment
of UC and its relapse.