Boosting luteolin bioavailability via P-glycoprotein efflux inhibition: a self-microemulsifying drug delivery systems

INTRODUCTION: The poor bioavailability of luteolin, a potent flavonoid with antioxidant and anti-inflammatory properties, hinders its therapeutic potential. The primary barriers to its absorption are its low solubility and active efflux by P-glycoprotein (P-gp) in the gastrointestinal tract. OBJECTIVES: To overcome these absorption barriers, we developed a functional self-microemulsifying drug delivery system (SME) incorporating D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), aiming to simultaneously enhance solubility, inhibit P-gp efflux, and improve the oral bioavailability and therapeutic efficacy of luteolin. METHODS: A TPGS-based luteolin-SME was prepared via self-assembly and characterized for particle size, stability, release profile, and antioxidant capacity. Cellular absorption mechanisms, permeability, and P-gp inhibition were evaluated using Caco-2 monolayers and molecular docking. Pharmacokinetics and biodistribution were assessed in rats, and therapeutic efficacy was examined in a lipopolysaccharide-induced inflammation model. RESULTS: The optimized luteolin-SME formed uniform nanodroplets (