Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Clin Pharmacol Ther
2020 Jan 01;1071:227-237. doi: 10.1002/cpt.1588.
Show Gene links
Show Anatomy links
Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1.
Chen M
,
Neul C
,
Schaeffeler E
,
Frisch F
,
Winter S
,
Schwab M
,
Koepsell H
,
Hu S
,
Laufer S
,
Baker SD
,
Sparreboom A
,
Nies AT
.
???displayArticle.abstract???
Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small-molecule multikinase inhibitor sorafenib is associated with large interindividual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter (OCT1; gene SLC22A1) has been proposed as a 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.
Robert-Bosch Foundation, Stuttgart, Germany, Interfaculty Centre for Pharmacogenomics and Pharma Research (ICEPHA), Grant Tübingen-Stuttgart, Germany, Deutsche Forschungsgemeinschaft (DFG) EXC2180-390900677, R01CA138744 National Institutes of Health (NIH), R01CA215802 National Institutes of Health (NIH), R01 CA138744 NCI NIH HHS , R01 CA215802 NCI NIH HHS , R01 CA187176 NCI NIH HHS
Al-Abdulla,
Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib.
2019, Pubmed
Al-Abdulla,
Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib.
2019,
Pubmed
Baker,
Pharmacokinetic considerations for new targeted therapies.
2009,
Pubmed
Billington,
Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC-MS/MS Proteomics.
2018,
Pubmed
Bins,
Influence of OATP1B1 Function on the Disposition of Sorafenib-β-D-Glucuronide.
2017,
Pubmed
Boudou-Rouquette,
Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis.
2012,
Pubmed
Bruix,
Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies.
2017,
Pubmed
Drenberg,
Integrating clinical pharmacology concepts in individualized therapy with tyrosine kinase inhibitors.
2013,
Pubmed
El-Serag,
Hepatocellular carcinoma.
2011,
Pubmed
Geier,
The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma.
2017,
Pubmed
Grimm,
Organic Cation Transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment.
2016,
Pubmed
Haralampiev,
The interaction of sorafenib and regorafenib with membranes is modulated by their lipid composition.
2016,
Pubmed
Heise,
Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance.
2012,
Pubmed
Herraez,
Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib.
2013,
Pubmed
,
Xenbase
Hu,
Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters.
2009,
Pubmed
,
Xenbase
Inaba,
Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia.
2011,
Pubmed
Johnston,
Selective inhibition of human solute carrier transporters by multikinase inhibitors.
2014,
Pubmed
Jouan,
Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells.
2016,
Pubmed
König,
Transporters and drug-drug interactions: important determinants of drug disposition and effects.
2013,
Pubmed
Lathia,
Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics.
2006,
Pubmed
Liu,
Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.
2006,
Pubmed
Llovet,
Sorafenib in advanced hepatocellular carcinoma.
2008,
Pubmed
Lozano,
Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition.
2018,
Pubmed
Macias,
Role of drug transporters in the sensitivity of acute myeloid leukemia to sorafenib.
2018,
Pubmed
Margaillan,
Quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues.
2015,
Pubmed
Martinez Molina,
Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay.
2013,
Pubmed
Mateus,
Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery.
2017,
Pubmed
Minematsu,
Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins.
2011,
Pubmed
Namisaki,
Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma.
2014,
Pubmed
Nies,
Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs).
2011,
Pubmed
Nies,
Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver.
2009,
Pubmed
Nies,
Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1).
2014,
Pubmed
,
Xenbase
Nies,
Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy.
2011,
Pubmed
Nies,
Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1).
2008,
Pubmed
Olson,
Beta galactosidase complementation: a cell-based luminescent assay platform for drug discovery.
2007,
Pubmed
Pargellis,
Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site.
2002,
Pubmed
Rodrigues,
The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells.
2009,
Pubmed
Schaeffeler,
DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma.
2011,
Pubmed
Sprowl,
A phosphotyrosine switch regulates organic cation transporters.
2016,
Pubmed
Strumberg,
Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.
2007,
Pubmed
Swift,
Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites.
2013,
Pubmed
Takano,
Human erythrocyte nucleoside transporter ENT1 functions at ice-cold temperatures.
2010,
Pubmed
Tomonari,
MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma.
2016,
Pubmed
Vasilyeva,
Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b.
2015,
Pubmed
Wilhelm,
Discovery and development of sorafenib: a multikinase inhibitor for treating cancer.
2006,
Pubmed
Zimmerman,
Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide.
2013,
Pubmed
Zimmerman,
Ontogeny and sorafenib metabolism.
2012,
Pubmed
