The involvement of multidrug and toxin extrusion protein 1 in the distribution and excretion of berberine

Abstract

1. Berberine (BBR), an isoquinoline alkaloid, has demonstrated multiple clinical pharmacological actions. As a substrate of multiple transporters in the liver, BBR is rarely excreted into the bile but can be found in the urine. The purpose of the present study was to investigate the role of multidrug and toxin extrusion protein 1 (MATE1) in the transport of BBR in the liver and kidney.

2. Using human MATE1 (hMATE1)-transfected HEK293 cells, BBR was shown to be a substrate of hMATE1 (K_m = 4.28 ± 2.18 μM). In primary rat hepatocytes, pH-dependent uptake and efflux studies suggested that the transport of BBR was driven by the exchange of H⁺ and involved Mate1. In rats, we found that pyrimethamine (PYR), an inhibitor of Mate1, increased hepatic and renal distribution of BBR and decreased systematic excretion of BBR.

3. These findings indicated that BBR is a substrate of MATE1 and that hepatic and renal Mate1 promote excretion of BBR into bile and urine, respectively. In conclusion, Mate1 plays a key role in the distribution and excretion of BBR, and we speculate that drug–drug interactions (DDIs) caused by MATE1 may occur between BBR and other co-administered drugs.

Keywords:

• Berberine
• MATE1
• hepatobiliary distribution
• excretion
• DDIs

Acknowledgments

The authors thank Dr. Xining Yang (US Food and Drug Administration) for his help in providing valuable advice to improve this manuscript.

Declaration of interest

No conflicts of interest, financial or otherwise, are declared by the authors. This work was supported by the National Natural Science Foundation of China under Grant Nos. 81302836 and 81573499 and by the National High Technology Research and Development Program of China under Grant No. 2013AA032202.