The inhibitory effects of five alkaloids on the substrate transport mediated through human organic anion and cation transporters

Abstract

1. Human solute carrier transporters (SLCs) are important membrane proteins mediate the cellular transport of many endogenous and exogenous substances. Organic anion/cation transporters (OATs/OCTs) and organic anion transporting polypeptides (OATPs) are essential SLCs involved in drug influx. Drug–drug/herb interactions through competing for specific SLCs often lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In this study, we comprehensively investigated the inhibitory effects of five clinically relevant alkaloids (dendrobine, matrine, oxymatrine, tryptanthrin and chelerythrine) on the substrate transport through several OATs/OCTs and OATPs.

2. We performed transport functional assay and kinetic analysis on the HEK-293 cells over-expressing each SLC gene.

3. Our data showed tryptanthrin significantly inhibited the transport activity of OAT3 (IC₅₀ = 0.93 ± 0.22 μM, K_i = 0.43 μM); chelerythrine acted as a potent inhibitor to the substrate transport mediated through OATP1A2 (IC₅₀ = 0.63 ± 0.43 μM, K_i = 0.60 μM), OCT1 (IC₅₀ = 13.60 ± 2.81 μM) and OCT2 (IC₅₀ =10.80 ± 1.16 μM).

4. Our study suggested tryptanthrin and chelerythrine could potently impact on the drug transport via specific OATs/OCTs. Therefore, the co-administration of these alkaloids with drugs could have clinical consequences due to drug–drug/herb interactions. Precautions should be warranted in the multi-drug therapies involving these alkaloids.

Keywords:

• Organic anion transporter
• organic anion transporting polypeptides
• organic cation transporter
• solute carrier transporters

Acknowledgements

The authors thank A/Prof. Wei Zhou (Guiyang Medical University, Guizhou, China) for providing the alkaloids. The authors thank the financial support from the International collaborative grant of the Science and Technology Foundation of Guizhou Province, China, and the internal funding of the Faculty of Pharmacy, University of Sydney, Australia.

Declaration of interest

The authors declare no conflict of interest.

Science and Technology Foundation of Guizhou Province10.13039/501100004001, University of Sydney, 10.13039/501100001774