Organic anion-transporting polypeptides contribute to the hepatic uptake of berberine

Abstract

1. The purpose of this study was to investigate the mechanism of hepatic uptake of berberine. Berberine accumulation in hepatocytes was found to be highly dependent on active uptake, which could not be explained by liver organic cation transporter (OCT) alone.

2. Our studies indicated that berberine uptake was significantly suppressed by rifampicin, cyclosporine A and glycyrrhizic acid, which act as specific inhibitors of different Oatp isoforms (Oatp1a1, Oatp1a4 and Oatp1b2) in rat hepatocytes. The combination of OCT and OATP inhibitors further reduced berberine accumulation in both rat and human hepatocytes. The uptake of berberine could be increased in human HEK293-OATP1B3 but not in OATP1B1-transfected HEK 293 cells.

3. Rifampicin could reduce the berberine liver extraction ratio (ER) and double its concentration in the effluent in isolated rat livers. Further in vivo study indicated that berberine plasma exposure could be significantly increased by co-administration of the OATP inhibitor rifampicin or the substrate rosuvastatin.

4. In conclusion, this study demonstrated that both OCT and OATP contribute to the accumulation of berberine in the liver. OATPs may have important roles in berberine liver disposition and potential clinically relevant drug--drug interactions.

• Berberine
• organic cation transporter
• organic anion-transporting polypeptides
• primary hepatocytes

Acknowledgements

We would like to express our sincere thanks to Dr. Peihua Sun from Pharma Resources Co., Ltd. for help with the studies in OATP1B1- and OATP1B3-transfected cell lines.

Declaration of interest

The authors declare no conflict of interest. This research was supported by National Natural Science Foundation of China (Grant No. 81302836), the Leading Science and Technology Projects (Grant No XDA01030600), the State Key Program of the National Science Foundation of China (Grant No 81030065), the Hundred Talents Program of the Chinese Academy of Sciences, Major National Science and Technology Programs (Grant Nos 2012ZX09301001-006) and the National High Technology Research and Development Program of China (Grant No 2013AA032202).