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Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2

Hiroki Ohya1, Yoshihiko Shibayama, Jiro Ogura

  • 1Laboratory of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University.

Biological & Pharmaceutical Bulletin
|March 6, 2015
PubMed

Insights

Regorafenib is transported by organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). Understanding these transporter interactions is crucial for predicting regorafenib

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Regorafenib is a tyrosine kinase inhibitor used for advanced colorectal cancer and gastrointestinal stromal tumors.
  • Understanding drug transport mechanisms is vital for optimizing therapeutic efficacy and predicting drug interactions.

Purpose of the Study:

  • To investigate the involvement of specific transporters, namely OATP1B1 and MRP2, in the transport of regorafenib.
  • To elucidate the substrate preferences of regorafenib concerning these key drug transporters.

Main Methods:

  • Utilized engineered cell lines overexpressing OATP1B1 and MRP2 (HEK293/OATP1B1, LLC-PK1/MRP2) and their respective mock controls.
  • Assessed regorafenib's effect on the uptake of known substrates (e.g., estrone sulfate) and its own intracellular accumulation in the presence and absence of transporter inhibitors (e.g., MK571).
  • Determined regorafenib transport kinetics (Km, Vmax) using OATP1B1-overexpressing cells.

Main Results:

  • Regorafenib uptake was significantly higher in HEK293/OATP1B1 cells compared to controls, indicating OATP1B1-mediated transport.
  • Regorafenib inhibited estrone sulfate uptake by HEK293/OATP1B1 cells, confirming its role as an OATP1B1 substrate.
  • Regorafenib intracellular concentration was reduced in LLC-PK1/MRP2 cells, and this effect was reversed by an MRP2 inhibitor, identifying MRP2 as another key transporter.
  • No significant difference in regorafenib concentration was observed between HEK293/OATP1B3 and mock cells, suggesting OATP1B3 is not a significant transporter.

Conclusions:

  • Regorafenib is confirmed as a substrate for both OATP1B1 and MRP2.
  • The identified transporter interactions of regorafenib are likely to influence its pharmacokinetic profile.
  • Further investigation into these transporter roles may aid in personalized medicine approaches for patients treated with regorafenib.

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