Author information
1 Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
2 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
3 University of Tübingen, Tübingen, Germany.
4 iFIT Cluster of Excellence, University of Tübingen, Tübingen, Germany.
5 Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
6 Institute of Anatomy and Cell Biology and Department of Molecular Plant Physiology and Biophysics, University of Würzburg, Germany.
7 Department of Pharmaceutical and Medicinal Chemistry, University of Tübingen, Tübingen, Germany.
Abstract
Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small molecule multi-kinase inhibitor sorafenib is associated with large inter-individual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter OCT1 (gene SLC22A1) has been proposed as clinical biomarker of HCC response. Because proof is lacking that OCT1 transports sorafenib, we used a combinatorial approach to define how OCT1 contributes to sorafenib transport. Overexpression of functional OCT1 protein in Xenopus laevis oocytes and mammalian cell lines did not facilitate sorafenib transport. Otherwise, sorafenib considerably accumulated in liver cancer cell lines despite negligible OCT1 mRNA and protein levels. Sorafenib pharmacokinetics was independent of OCT1 genotype in mice. Finally, SLC22A1 mRNA expression was significantly reduced by DNA methylation in The Cancer Genome Atlas HCC cohort. These results clearly demonstrate OCT1-independent cellular sorafenib uptake indicating that OCT1 is apparently not a valid biomarker of sorafenib response in HCC.