Renal vectorial transport of berberine mediated by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 (MATE1) in rats

Abstract

Berberine, a well-known plant alkaloid derived from Rhizoma coptidis, has potential applications as a therapeutic drug for diabetic nephropathy. However, the transporter-mediated renal transport of berberine remains largely unclear. This study aimed to investigate the renal transport mechanism of berberine using transfected cells, kidney slices and animal experiments. In Madin-Darby canine kidney (MDCK) cells stably expressing rat OCT2 (MDCK-rOCT2) and kidney slices, saturable and non-saturable uptake of berberine was observed, and corticosterone could inhibit the uptake of berberine, with IC 50 values of 0.1 μM and 147.9 μM, respectively. In double-transfected cells, the cellular accumulation of berberine into MDCK-rOCT2 and MDCKrOCT2-rMATE1 (MDCK cells stably expressing rOCT2 and rMATE1) cells was significantly higher than the uptake into MDCK cells. Meanwhile, berberine transcellular transport was considerably higher in double-transfected MDCK-rOCT2-rMATE1 cells than in MDCK and MDCK-rOCT2 cells. Corticosterone for MDCK-rMATE1 and MDCK-MDR1 and pyrimethamine for MDCKrMATE1 at high concentrations could inhibit the efflux of berberine. In animal experiments, compared with the berberine alone group, the cumulative urinary excretion of berberine significantly decreased in the corticosterone or pyrimethamine pretreatment groups. In the rat kidney, pyrimethamine increased, and a low dose of corticosterone (5 mg/kg) decreased, the berberine concentration. However, there was no apparent change in the renal concentration of berberine in rats pretreated with corticosterone (10 or 20 mg/kg). Thus, berberine is not only a substrate of OCT2 and P-glycoprotein, but is also a substrate of MATE1. Both OCT2 and MATE1 mediate the renal vectorial transport of berberine.

Pharmacokinetic of berberine, the main constituent of Berberis vulgaris L.: A comprehensive review

“…Moreover, pyrimethamine as a MATE 1 suppressor, led to a decrease in the urinary excretion of berberine (Shi et al, 2018).…”

“…Co‐administration of an OCT2 inhibitor (corticosterone) and berberine in rats, resulted in a decrease in the urinary excretion of berberine. Moreover, pyrimethamine as a MATE 1 suppressor, led to a decrease in the urinary excretion of berberine (Shi et al, 2018).…”

Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment

“…Similarly, OCT2 mediated BBR renal carrier transport. As an OCT2 inhibitor, corticosterone could inhibit BBR efflux at high concentrations [ 118 , 119 ]. Experimental studies have found that, in the absence of inhibitors (e.g., pyrimethamine and corticosterone), BBR could induce pharmacokinetic interactions by combining with other drugs to inhibit OCT- and MATE1-mediated transport [ 120 , 121 ].…”

The mitohormetic response as part of the cytoprotection mechanism of berberine

“…In this way, it was difficult for Ber to rapidly and passively diffuse through cell membranes (Berberine 1991;Zhang et al 2014). However, as a substrate of organic cation transporter 1 (OCT1, SLC22A1 gene) and organic cation transporter 2 (OCT2, SLC22A2 gene), Ber could be taken up into cells at a relatively fast rate (Nies et al 2008;Shi et al 2018). OCT2 is also expressed in the central nervous system.…”