Polyethylene glycol 400 improves the bioavailability and anti-inflammatory activity of quercetin by modulating metabolic enzymes and efflux transporters.

Quercetin (QUE) is a widely distributed natural bioactive flavonoid. However, its clinical application is restricted by poor oral bioavailability. Low aqueous solubility, hepatic UDP-glucuronosyltransferase (UGT)-mediated glucuronidation and breast cancer resistance protein (BCRP)- and multidrug resistance-associated protein 2 (MRP2)-mediated intestinal efflux collectively restrict systemic exposure of QUE. Polyethylene glycol 400 (PEG 400), a common solubilizing excipient for flavonoid formulations, modulates the activity of UGTs and efflux transport activity to alter the pharmacokinetics of flavonoids like baicalin. However, whether PEG 400 exerts similar regulatory effects on QUE remains unclear. Herein, we evaluated the impact of PEG 400 (2000 mg/kg) on the pharmacokinetics and tissue distribution of QUE (40 mg/kg) in rats using UPLC-MS/MS and spatial mass spectrometry imaging. In vitro assays using rat liver microsomes, UGT1A9-overexpressing HepG2 cells, and Caco-2 monolayers were conducted to elucidate the underlying mechanisms, and a carrageenan-induced paw edema model was employed to assess the anti-inflammatory efficacy of QUE co-administered with PEG 400. Our results demonstrated that PEG 400 markedly enhanced the area under the plasma concentration-time curve (AUC0-t) of QUE and its major metabolite quercetin-3-O-β-D-glucuronide (Q3GA) by 9.9-fold and 15.8-fold, respectively, and altered their tissue distribution. In vitro assays demonstrated that PEG 400 increased UGT1A9 activity and suppressed BCRP/MRP2 activity and expression. Carrageenan-induced paw edema experiments further confirmed that PEG 400 enhanced QUE's anti-inflammatory efficacy. In conclusion, our findings suggest that altered solubility, UGT1A9-mediated glucuronidation and BCRP/MRP2-mediated efflux may jointly contribute to the elevated systemic exposure and anti-inflammatory efficacy of QUE co-administered with PEG 400.