Article
Cellular uptake of sorafenib is independent of major human organic cation and organic anion uptake transporters of the hepatocyte
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Authors
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Claudia Neul
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Stuttgart, Germany
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Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Stuttgart, Germany
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Stefan Laufer
- Dept. of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany
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Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Dept. of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany
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Anne Nies
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Stuttgart, Germany
| Published: | September 24, 2015 |
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Outline
Text
Purpose: The orally active multikinase inhibitor sorafenib significantly increases survival of patients with advanced clear-cell renal or hepatocellular carcinomas [1]. Sorafenib has a dual mode of action: (i) it inhibits cell division and cell proliferation by inhibiting the RAF/MEK/ERK pathway and (ii) it also targets the VEGF receptor, which causes a reduction of tumor angiogenesis so that the blood supply of the tumor cells is inhibited. After oral administration, sorafenib undergoes either glucuronidation or oxidative metabolism, resulting in the primary metabolites sorafenib glucuronide and sorafenib N-oxide, respectively.
As sorafenib targets intracellular kinases, it is very important to understand how sorafenib passes the cell membrane of tumor cells. Several hepatic uptake transporters, i.e. organic cation transporter OCT1 [2], [3] and organic anion transporting polypeptides OATP1B1 and OATP1B3 [4] have been suggested to be involved in sorafenib uptake, but there are still conflicting data [5]. We therefore used transporter-overexpressing cell lines to clarify whether these uptake transporters are involved in sorafenib uptake.
Experimental design: Cellular accumulation of radiolabeled sorafenib was analyzed using the mammalian cell line HEK293 stably expressing OCT1 [6], or OATP1B1, OATP1B3 and OATP2B1 [7] as well as human hepatocellular carcinoma cells (HepG2, HuH7).
Results: The overexpression of the functional transporter proteins in HEK cells did not result in an increased cellular uptake of sorafenib. In contrast, HuH7 cells and HepG2 cells, in which expression of OCT1 and OATPs is low, showed a considerable sorafenib uptake.
Conclusion: Our results show that uptake of sorafenib is independent of the expression of the tested transporters and that other, yet unidentified transporters are responsible for cellular sorafenib uptake.
Supported by the Robert Bosch Foundation, Stuttgart, Germany and the ICEPHA Grant Tübingen-Stuttgart, Germany
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