Co‐administration of nuciferine reduces the concentration of metformin in liver via differential inhibition of hepatic drug transporter OCT1 and MATE1

Abstract Nuciferine (NF), one of the main and effective components in Nelumbo nucifera Gaertn. leaf extracts, is a promising drug candidate for the treatment of obesity‐related diseases, while metformin is a first line therapeutic drug for type 2 diabetes mellitus. Since nuciferine and metformin are likely to be co‐administered, the aim of the present study was to evaluate whether co‐administration of nuciferine would influence the liver (target tissue) distribution and the anti‐diabetic effect of metformin by inhibiting hepatic organic cation transporter 1 (OCT1) and multidrug and toxin extrusion 1 (MATE1). The data demonstrated that nuciferine significantly reduced metformin accumulation in MDCK cells stably expressing human OCT1 (MDCK‐hOCT1) or hMATE1 (MDCK‐hMATE1), and primary cultured mouse hepatocytes. Furthermore, the presence of nuciferine in the basal compartment caused a concentration‐dependent reduction of intracellular metformin accumulation in MDCK‐hOCT1/hMATE1 cell monolayers. Compared with the metformin treatment‐alone group, co‐administration of nuciferine (40 mg/kg) markedly reduced the metformin concentration in mouse livers at 30 and 60 min after a single oral dose of metformin (200 mg/kg), and subsequently impaired the glucose‐lowering effect of metformin (200 mg/kg), but the glucose‐lowering effect became no different at 90 and 120 min. Therefore, nuciferine influenced the liver concentration and glucose‐lowering effect of metformin only for a period of time after dose, administration of nuciferine and metformin with an interval might prevent the drug–drug interaction mediated by OCT1 and MATE1.