Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1093
Peer-review started: December 12, 2017
First decision: December 27, 2017
Revised: December 31, 2017
Accepted: January 24, 2018
Article in press: January 24, 2018
Published online: March 14, 2018
To design colon-targeted codrugs of mycophenolic acid (MPA) and aminosugars as a safer option to mycophenolate mofetil (MMF) in the management of inflammatory bowel disease.
Codrugs were synthesized by coupling MPA with aminosugars (D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates (in vitro) and rat blood (in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease control.
The prodrugs resisted activation in HCl buffer (pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer (pH 7.4) and intestinal homogenates. Incubation with colon homogenates (in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine (MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA.
The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid.
Core tip: Mycophenolic acid (MPA), an immunosuppressant and its morpholinoethyl ester prodrug: mycophenolate mofetil are under investigation for the treatment of inflammatory bowel disease (IBD). Diarrhea and local gut toxicity are their major setbacks. The present work focused on the synthesis of colon-targeted prodrugs wherein MPA was bio-reversibly linked with aminosugars to mask the carboxyl group of MPA responsible for gastrointestinal side effects. The synthesized prodrugs exhibited a significant mitigating effect on 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats compared to MPA. The absence of pancreatitis, hepatitis and the gastro-sparing nature of the prodrugs emphasize their potential which could be investigated further for the management of IBD.