Non-systemic drugs: a critical review

Area of Science:

• Pharmacology
• Gastroenterology
• Drug Development

Background:

• Non-systemic drugs act exclusively within the intestinal lumen, avoiding systemic circulation.
• Early non-systemic agents included polymeric resins for ion and bile acid sequestration.
• The field has advanced to non-absorbable small molecules and peptides targeting luminal targets.

Purpose of the Study:

• To review non-absorbable agents, their development stages, therapeutic potential, and limitations.
• To highlight the evolution of non-systemic drug design and its opportunities.
• To discuss challenges in controlling drug entry into systemic circulation.

Main Methods:

• Review of existing literature on non-systemic drugs.
• Analysis of drug design principles for luminal agents.
• Examination of pharmacokinetic-pharmacodynamic complexities in the GI tract.

Main Results:

• Non-systemic agents offer reduced toxicity risks for treating metabolic, GI, and infectious disorders.
• Challenges include managing drug interactions within the GI tract and preventing systemic leakage.
• Identification of intestinal receptors and transporters is crucial for future development.

Conclusions:

• Non-systemic therapeutics present a promising avenue for addressing unmet medical needs with improved safety profiles.
• Further research into intestinal targets and drug delivery will drive innovation in this field.
• Understanding and controlling non-transcellular leakage is key to optimizing non-systemic drug efficacy.