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

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.

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.

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.

The optimized luteolin-SME formed uniform nanodroplets (<50 nm) with high stability and achieved a 4.3-fold higher cumulative release compared to free luteolin. In Caco-2 cells, the formulation significantly enhanced cellular uptake and permeability, primarily via clathrin- and caveolae-mediated endocytosis, and effectively inhibited P-gp efflux. Pharmacokinetically, luteolin-SME provided a 29-fold increase in relative bioavailability (AUC 247.729 vs. 8.628 mg/L·h) and a 16-fold higher Cmax (27.546 mg/L) over free luteolin. In the lipopolysaccharide-induced inflammation model, luteolin-SME markedly attenuated oxidative stress, reducing the TNF-α, IL-6, and IL-1β levels by approximately 37%, 26%, and 39%, respectively.

The TPGS-functionalized SME effectively overcame the major absorption barriers of luteolin by integrating nanocarrier-enhanced solubilization with active P-gp inhibition. This dual strategy resulted in unprecedented oral bioavailability enhancement and potent efficacy. Our study establishes a robust and clinically promising delivery platform for luteolin and other poorly soluble, efflux-limited bioactive compounds, offering a practical approach to enhance oral therapy for inflammation-related diseases.