title: Investigation of mitigating effect of colon-specific prodrugs of boswellic acid on 2,4,6-trinitrobenzene sulfonic acid-induced colitis in Wistar rats: Design, kinetics and biological evaluation.
abstract: OBJECTIVE
  To develop a colon-targeting bioreversible delivery system for β-boswellic acid (BBA) and explore utility of its prodrugs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.
  
  
  METHODS
  Synthesis of 4 co-drugs of BBA with essential amino acids was achieved by CDI coupling, followed by their spectral characterization.In vitrokinetics were studied by HPLC in aqueous buffers, homogenates of gastrointestinal tract and fecal matter.In vivokinetic studies were performed in Wistar rat plasma, urine and feces. The prodrugs were screened in TNBS-induced colitis modeled Wistar rats. Statistical significance was assumed atP< 0.05,P< 0.01,P< 0.001 when compared with disease controls using one-way and two-way ANOVAs.
  
  
  RESULTS
  Prodrugs were stable in 0.05 mol/L HCl buffer (pH 1.2) and stomach homogenates. Negligible hydrolysis was observed in phosphate buffer and intestinal homogenates. Substantial release (55%-72% and 68%-86%) of BBA was achieved in rat fecal matter and homogenates of colon.In vivostudies of BBA with L-tryptophan (BT) authenticated colon-specific release of BBA. But, surprisingly substantial concentration of BBA was seen to reach the systemic circulation due to probable absorption through colonic mucosa. Site-specifically enhanced bioavailability of BBA could be achieved in colon, which resulted in demonstration of significant mitigating effect on TNBS-induced colitis in rats without inducing any adverse effects on stomach, liver and pancreas. Prodrug of BT was found to be 1.7% (P< 0.001) superior than sulfasalazine in reducing the inflammation to colon among all prodrugs tested.
  
  
  CONCLUSIONS
  The outcome of this study strongly suggests that these prodrugs might have dual applicability to inflammatory bowel disease and chronotherapy of rheumatoid arthritis.
authors.affiliation: Ajinkya Sarkate, Suneela S Dhaneshwar, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India.
authors.forename: Ajinkya
authors.initials: A
authors.lastname: Sarkate
authors.affiliation: Ajinkya Sarkate, Suneela S Dhaneshwar, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India.
authors.forename: Suneela S
authors.initials: SS
authors.lastname: Dhaneshwar
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D005243:Feces; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D007700:Kinetics; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid; D014315:Triterpenes / Q000008:administration & dosage*
chemical_list: D000577:Amides; D011355:Prodrugs; D014315:Triterpenes; C054625:boswellic acid; D014302:Trinitrobenzenesulfonic Acid
keywords: Amino acids; Boswellic acid; Colon-targeting; Complementary and alternative medicine; Inflammatory bowel disease; Mutual prodrugs; TNBS-induced colitis