Involvement of P-glycoprotein and multidrug and toxin extrusion protein 1 in hepatic and renal berberine efflux in mice

Abstract

Berberine (BBR) is a natural alkaloid and commonly used drug with extensive pharmacological effects. The blood exposure of BBR is known to be extremely low while its tissue exposure is extremely high, especially in the liver and kidney where its uptake is mediated by organic cation transporters and organic anion-transporting polypeptides. However, the efflux mechanism in the liver and kidney is not clear. Therefore, the present study was designed to investigate the mechanism of hepatic and renal efflux of BBR. A transport assay of BBR using rat Madin–Darby canine kidney (MDCK)-multidrug and toxin extrusion protein 1 (rMate1) cells and a transcellular transport assay using MDCK-multidrug resistance protein 1 (MDR1) cells were conducted to evaluate the efflux mechanism. Tissue distribution and excretion of BBR were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of specimens from C57BL/6J mice co-administered BBR and itraconazole (ITZ, a P-glycoprotein, P-gp inhibitor) or pyrimethamine (PYR, a MATE1 inhibitor). The inhibitory effect of ITZ and PYR on the combined effects of BBR with P-gp and MATE1 was verified using Glide docking within the Schrodinger program. BBR uptake was observed to be pH-, time-, temperature- and concentration-dependent and was inhibited by PYR in MDCK-rMate1 cells. ITZ significantly decreased the Papp_b→a values of BBR in MDCK-MDR1 cells. Co-administration with PYR or ITZ increased the concentration of BBR in the liver and kidney and decreased its excretion in urine and bile in mice. In addition, co-administration with ITZ increased the plasma concentration of BBR. Both ITZ and PYR had higher docking scores than BBR did to P-gp and rMate1, respectively and separately prevented the combination of BBR with rMate1 and P-gp. This study indicated that both MATE1 and P-gp mediated hepatic and renal efflux of BBR. These results provide salient information that enhances the understanding of the pharmacokinetics properties of BBR and its interaction with other drugs.