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The herbal remedy St. John's wort (SJW) is used in the treatment of mild depressive symptoms and is known for its drug-drug interaction potential when enhanced expression of CYP3A4 modifies clearance of concomitantly applied substrate drugs. Hyperforin is one constituent of SJW that alters CYP3A4 expression by activation of the nuclear receptor pregnane X receptor (PXR). However, little is known about the transmembrane transport of hyperforin. One membrane protein that modulates cellular entry of drugs is the organic aniontransporting polypeptide (OATP) 2B1. It was the aim of this study to test whether hyperforin interacts with this transport protein. Transport inhibition studies and competitive counterflow experiments suggested that hyperforin is a substrate of OATP2B1. This notion was validated by showing that the presence of OATP2B1 enhanced the hyperforin-induced PXR activation in cell-based luciferase assays. Moreover, in Caco-2 cells transcellular transport of the known OATP2B1 substrate atorvastatin was changed in the presence of hyperforin, resulting in an increased efflux ratio. Eleven commercially available SJW formulations were assessed for their influence on OATP2B1mediated transport of estrone 3-sulfate and for their impact on CYP3A4 promoter transactivation. The correlation between effect size and the hyperforin content as determined by highperformance liquid chromatography with ultraviolet detection suggested that hyperforin is the major determinant. Our results indicate an interaction between hyperforin and OATP2B1, which is not only known to contribute to hepatocellular uptake but also to intestinal absorption of its substrates. These findings extend the complexity of mechanisms that should be considered when evaluating the interaction potential of SJW preparations.This work was conducted without support by external funding agencies. None of the authors has a conflict of interest to declare. https://doi.org/10. 1124/mol.118.114066. s This article has supplemental material available at molpharm. aspetjournals.org.