Quercetin Simultaneously Inhibited Cytochrome P450 and P-Glycoprotein to Improve the Pharmacokinetics of Osthole in Rat Plasma

Plant-based medicines derived from traditional Chinese medicine have garnered widespread attention for their potential in the prevention and treatment of various diseases, offering superior oral bioavailability compared to the use of single drug formulations. Nonetheless, the precise biological mechanisms and interactions between compounds and enzymes remain inadequately understood. This study delves into the inhibitory interactions of quercetin with cytochrome P450 and P-glycoprotein, leading to a synergistic enhancement of osthole bioavailability in rat plasma. The results indicate that quercetin demonstrates concentration-dependent and uncompetitive inhibition of liver microsomal cytochrome P450 proteins 3A, with an observed IC 50 value of 34.17 μM. Additionally, quercetin notably suppresses the expression of P-glycoprotein in the small intestines of rats, resulting in a significant 52.9% reduction ( p  < 0.001) and a corresponding downregulation of its associated mRNA Mdr1b level. The administration of quercetin alongside osthole in rats leads to a marked increase of over 80% ( p  < 0.001) in osthole blood concentration, as determined by pharmacokinetic analysis, surpassing the effects of pure osthole usage. This multifunctional attribute of quercetin, along with the observed synergistic changes in pharmacokinetics, holds promise for shedding light on the interplay of drug–drug/enzyme interactions in the context of medicinal plants. Graphical abstract