A colon-targeted prodrug, 4-phenylbutyric acid-glutamic acid conjugate, ameliorates 2,4-dinitrobenzenesulfonic acid-induced colitis in rats

Soojin Kim, Seunghyun Lee, Hanju Lee, Sanghyun Ju, Sohee Park, Doyoung Kwon, Jin Wook Yoo, In Soo Yoon, Do Sik Min, Young Suk Jung, Yunjin Jung

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield 4-PBA-glutamic acid (PBA-GA) and 4-PBA-aspartic acid (PBA-AA) conjugates. The PBA derivatives were converted to 4-PBA in the cecal contents, and the conversion was greater with PBA-GA than that with PBA-AA. After oral administration of PBA-GA (oral PBA-GA), up to 2.7 mM PBA was detected in the cecum, whereas 4-PBA was not detected in the blood, indicating that PBA-GA predominantly targeted the large intestine. In 2,4-dinitrobenzenesulfonic acid-induced colitis in rats, oral PBA-GA alleviated the damage and inflammation in the colon and substantially reduced the elevated levels of ER stress marker proteins in the inflamed colon. Moreover, PBA-GA was found to be as effective as the currently used anti-IBD drug, sulfasalazine. In conclusion, PBA-GA is a colon-targeted prodrug of 4-PBA and is effective against rat colitis probably via the attenuation of ER stress in the inflamed colon.

Original languageEnglish
Article number843
Pages (from-to)1-16
Number of pages16
JournalPharmaceutics
Volume12
Issue number9
DOIs
Publication statusPublished - 2020 Sept

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

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