title: Investigating Drug Repositioning Approach to Design Novel Prodrugs for Colon-specific Release of Fexofenadine for Ulcerative Colitis.
abstract: 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.
  
  
  METHODS
  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 Wistar rats.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune-411 038, Maharashtra, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune-411 038, Maharashtra, India.
authors.forename: Suneela S
authors.initials: SS
authors.lastname: Dhaneshwar
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects*; D065546:Drug Liberation; D058492:Drug Repositioning; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D011355:Prodrugs; D016593:Terfenadine; C093230:fexofenadine
keywords: Amide linkage; amino acid; antihistaminic; fexofenadine; histamine; repositioning; ulcerative colitis