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REVIEW ARTICLE

Advancements in intestinally restricted drugs: Applications, targets, and design strategies

Ke Zhang1 ,  Haixin Chen1 ,  Shengjie Li2 ,  Menglin Wan1 ,  Peilin Huo1 ,  Kai Tang1 ,  Jing Xie3 ,  Chang Liu3 ,  Shizhen Zhao1,3* ,  Xinrui Lv1*
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1 The First Affiliated Hospital of Henan University, Kaifeng, Henan, China
2 School of Pharmacy, Henan University, Kaifeng, Henan, China
3 Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
GPD, 5058 https://doi.org/10.36922/gpd.5058
Submitted: 7 October 2024 | Revised: 16 January 2025 | Accepted: 22 January 2025 | Published: 17 February 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Drug safety is of paramount importance in the pharmaceutical industry, as it often hinders the successful introduction of new drug candidates into the market. Intestinally restricted drugs, also known as non-systemic drugs, are orally administered compounds that exert therapeutic effects specifically within the intestinal lumen, thereby circumventing side effects associated with systemic exposure. These drugs offer innovative solutions for unmet medical needs in drug development while minimizing toxicity risks. This review provides an overview of the applications of intestinally restricted drugs for inflammatory diseases, irritable bowel syndrome, colorectal cancer, and other digestive system ailments. Based on design strategies, these drugs can be classified into five categories, including high molecular weight compounds, highly polar or positively charged compounds, highly lipophilic and low water solubility compounds, intestinal soft drugs, and intestinal prodrugs. Specifically, it focuses on the design strategies of these drugs and presents an analysis of these strategies through representative drugs from each category. Due to the complex physiological environment of the gastrointestinal tract and the need for precise drug targeting, developing orally administered intestinally restricted drugs remains a significant challenge for scientists. This review enhances understanding of intestinally restricted drugs and offers a valuable reference for advancing their development.

Graphical abstract
Keywords
Intestinally restricted drugs
Design strategies
Non-systemic drugs
Drug safety
Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81903444), the Key Science and Technology Program of Henan Province (Grant No. 232102310398), the Natural Science Foundation of Henan (Grant No. 242300420100), the Key Scientific Research Projects of Institutions of Higher Education in Henan Province (Grant No. 24A350004), the Medical Scientific and Technological Research Project of Henan Province (Grant No. SBCJ202303040), the Foundation of Science & Technology Department of Henan (Grant No. 202102310034), the Science and Technology Research Project of Kaifeng City (Grant No. 2303002), and the College Students’ Innovative Entrepreneurial Training Plan Program (Grant No. 20231022006).
Conflict of interest
The authors declare they have no competing interests.
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