Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport

Abstract

P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and VCR. However, the underlying mechanism is unclear. This study investigated the potential mechanism by which OPD improves P-gp-mediated drug transport. Molecular docking was performed to predict the binding force between OPD and P-gp and the contribution of OPD on P-gp activity. We observed the effect of OPD on the transport of VCR in MDCK-MDR1 cell monolayer and also measured the plasma pharmacokinetic parameters of DTX in the presence and absence of OPD by LC-MS/MS. Moreover, we further investigated the reversal mechanism of OPD on P-gp-mediated drug transport by determining the intracellular accumulation of Rhodamine-123 (Rh123) and P-gp ATPase activity as well as protein expression and mRNA level of P-gp. Our molecular docking results revealed that the binding force between OPD and P-gp was much lower than that between P-gp and verapamil (a P-gp substrate). The transport study in vitro indicated that OPD increased the flux of VCR across MDCK-MDR1 cell monolayer. The in vivo pharmacokinetic parameters data showed OPD increased the absorption of DTX. OPD activated P-gp ATPase activity and enhanced intracellular accumulation of Rh123 in MDCK-MDR1 cells. Western blotting and qRT-PCR outcomes indicated that OPD suppressed P-gp protein expression as well as downregulated P-gp mRNA level. Thus, OPD reverse P-gp-mediated drug transport via inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA level. Our results suggest that OPD could reverse P-gp-mediated drug resistance in tumor cells.

Inhibitory Effect of Imperatorin on the Pharmacokinetics of Diazepam In Vitro and In Vivo

“…Furocoumarins are a group of natural products that widely present in fruits, beverages, and herbs in different forms (Hung et al, 2017). Therefore, many components of furocoumarins influence the activities of P450, Pgp, organic cation/carnitine transporter, and organic anion transporter (Wang et al, 2012;Dong et al, 2018), which may cause drug interactions. Previous studies have used liquid-high-resolution mass spectrometry to detect dozens of metabolites, mainly oxidation products, in the urine of rats orally administered IMP (Qiao et al, 2013).…”

“…Furocoumarins are a group of natural products that widely present in fruits, beverages, and herbs in different forms ( Hung et al., 2017 ). Therefore, many components of furocoumarins influence the activities of P450, P-gp, organic cation/carnitine transporter, and organic anion transporter ( Wang et al., 2012 ; Dong et al., 2018 ), which may cause drug interactions.…”

Emodin enhances cisplatin sensitivity in non-small cell lung cancer through Pgp downregulation

“…Cells were harvested, resuspended in fresh medium, and stained with 5 µM rhodamine 123 (Sigma-Aldrich; Merck KGaA) for 30 min at 37°C. Cells were washed three times with PBS, and drug accumulation levels were determined by fluorescence microscopy (Leica Microsystems GmbH) ( 28 ). The fluorescence intensity was determined using ImageJ software (version 1.32; National Institutes of Health).…”

Oxypeucedanin: Chemotaxonomy, Isolation, and Bioactivities

“…Cytotoxicity of OP isolated from Zanthoxylum flavum also has been investigated against the HL-60 (IC 50 : 8.9 µg/mL) and Vero cell lines (no activity) [ 69 ]. According to Dong et al [ 106 ], multidrug resistance of the chemotherapeutic drugs comprising vincristine sulphate (VCR) and docetaxel (DTX) were mainly caused by P-glycoprotein. An MTT assay was applied to evaluate permeability (apical to basolateral side) of OP to Mardin Darby canine kidney (MDCK) cells.…”