Prodrug Approach as a Strategy to Enhance Drug Permeability.

Absorption and permeability are critical physicochemical parameters that must be balanced to achieve optimal drug uptake. These key factors are closely linked to the maximum absorbable dose required to provide appropriate plasma levels of drugs. Among the various strategies employed to enhance drug solubility and permeability, prodrug design stands out as a highly effective and versatile approach for improving physicochemical properties and enabling the optimization of biopharmaceutical and pharmacokinetic parameters while mitigating adverse effects. Prodrugs are compounds with reduced or no activity that, through bio-reversible chemical or enzymatic processes, release an active parental drug. The application of this technology has led to significant advancements in drug optimization during the design phase, and it offers broad potential for further development. Notably, approximately 13% of the drugs approved by the U.S. Food and Drug Administration (FDA) between 2012 and 2022 were prodrugs. In this review article, we will explore the application of prodrug strategies to enhance permeability, describing examples of market drugs. We also describe the use of the prodrug approach to optimize PROteolysis TArgeting Chimeras (PROTACs) permeability by using conjugation technologies. We will highlight some new technologies in prodrugs to enrich permeability properties, contributing to developing new effective and safe prodrugs.