Prodrug strategy: molecular design for improving oral drug absorption

Oral administration remains the most prevalent route of drug delivery due to its non-invasive nature and excellent patient compliance. However, the suboptimal bioavailability of many orally administered drugs poses a significant challenge, which can be attributed to complex absorption mechanisms involving factors such as solubility, permeability, first-pass metabolism, and efflux transporter effects. Consequently, exploring effective strategies to enhance oral drug absorption has become a major research focus. Among these, the prodrug approach has garnered significant attention for its versatility in optimizing drug properties. This article systematically reviews recent research progress in improving the oral bioavailability of drugs based on the prodrug strategy. It focuses on enhancing drug solubility, permeability, and metabolic stability through prodrug design, leveraging gastrointestinal transporter- mediated absorption mechanisms, and combining formulation strategies to further improve oral drug absorption. The aim is to provide a theoretical foundation and strategic support for related research and applications in this field.