Pharmaceutical excipients that alter intestinal drug Absorption: A systematic review of Excipient–Drug interactions

Pharmaceutical excipients have traditionally been considered pharmacologically inert components of drug formulations. However, accumulating evidence suggests that certain excipients can affect drug absorption in the gastrointestinal tract. In this systematic review, we comprehensively examined studies reporting the effects of excipients on oral drug absorption, with a focus on mechanistic insights and clinical relevance. Using a PubMed-based keyword search, approximately 180 relevant publications from the past 20 years were identified, of which only approximately 10 % involved human pharmacokinetic studies. Most of the data were derived from rodent models or in vitro systems, such as Caco-2 cells. The effect of excipients on drug absorption is broadly categorized into four mechanistic groups: permeability change/absorption enhancement, transporter modulation, metabolic enzyme interactions, and alterations in gastrointestinal transit time. Although many studies have reported that excipients can affect drug absorption, other studies have shown no significant impact. Even when an effect is observed, its clinical relevance should be evaluated based on the amount used and the validity of the experimental models. Notably, the potential interactions arising from combinations of excipients remain largely unexplored. To successfully develop bioequivalent formulations, it is important to assess these interactions early using appropriate models. Understanding the characteristics of each test system and utilizing appropriate modeling techniques may facilitate rational excipient selection during formulation development. • Drug–excipient interactions were broadly grouped into four mechanistic categories. • Only 10 % of 183 studies reviewed assessed excipient effects in clinical trials. • Most evaluations used rodent models or Caco-2 cell systems. • Mechanism-based assessment using appropriate models is essential. • Modeling & simulation may help predict clinical impact of excipient interactions.