Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2018; 24(10): 1093-1106
Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1093
Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats
Shakuntala Santosh Chopade, Suneela Sunil Dhaneshwar
Shakuntala Santosh Chopade, Suneela Sunil Dhaneshwar, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune 411038, India
Author contributions: Chopade SS and Dhaneshwar SS equally contributed to the conception and design of the study, acquisition, analysis and interpretation of data, drafted the article and made revisions related to the intellectual content of the manuscript.
Supported by Women Scientist Scheme-A (DST), No. SR/WOS-A/LS-1115/2014.
Institutional animal care and use committee statement: All animal experimentation was approved by the Institutional Animal Ethics Committee (IAEC-approval number: CPCSEA/PCH/15/2014-15) of Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune 411038, India.
Conflict-of-interest statement: The authors wish to declare no conflict of interest.
Data sharing statement: There are no additional data available in relation to this manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Suneela Sunil Dhaneshwar, BPharm, PhD, Professor, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune 411038, India.
Telephone: +91-20-25437237 Fax: +91-20-25439382
Received: December 11, 2017
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.

Keywords: Mycophenolic acid, Mutual prodrug, Inflammatory bowel disease, Mycophenolate mofetil

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.