Quercetin can serve as a CXR inhibitor to enhance florfenicol absorption by attenuating BCRP-mediated efflux in chickens

Breast cancer resistance protein (BCRP) efflux activity limits drug absorption and contributes to multidrug resistance. Targeting nuclear receptors to modulate BCRP expression offers a potential strategy to overcome this challenge. Although it is known that the chicken xenobiotic receptor (CXR) influences BCRP expression, the exact binding site and mechanism remain unclear. This study aims to clarify how CXR regulates BCRP transcription in chickens and to find natural CXR inhibitors to improve the absorption of BCRP-substrate drugs. Utilizing a dual-luciferase reporter assay, we identified a functional CXR response element located between -9567 and -9551 upstream of the chicken BCRP transcriptional start site. Using this element, a screening model was developed, which revealed that quercetin inhibits CXR transcriptional activity in a concentration-dependent manner. In vitro experiments demonstrated that quercetin significantly downregulated BCRP mRNA expression and reduced efflux efficiency in chicken hepatocytes. In vivo studies further confirmed that quercetin decreased BCRP expression in liver, kidney, and intestine. Furthermore, the use of a jejunal perfusion model showed that quercetin (20 mg/kg) significantly increased the apparent permeability coefficient of the BCRP substrate florfenicol from 0.32 to 0.59 (p < 0.01). Subsequent pharmacokinetic analyses revealed that coadministration with quercetin (20 mg/kg) significantly elevated the C_max from 7.24 to 10.00 μg/mL (p < 0.01) and the AUC_0-∞ from 25.09 to 44.60 h·μg/mL (p < 0.01) of florfenicol. This research elucidates the molecular mechanisms underpinning the CXR-BCRP transcriptional cascade and proposes an innovative strategy targeting nuclear receptors to enhance drug absorption.