Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1

Abstract

Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small molecule multikinase 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-

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

“…Solute carriers (SLC) play an essential role in the uptake of anticancer drugs. For instance, although a controversial study has reported the inability of organic cation transporter-1 (OCT1, SLC22A1 ) to transport sorafenib [ 8 ], others using Xenopus laevis oocytes and mammalian cells with stable expression of OCT1 have revealed that this transporter is involved in the uptake of sorafenib [ 9 , 10 ], but not regorafenib [ 10 ]. Reduced SLC22A1 expression and impaired OCT1 function, due to loss-of-function mutations and aberrantly spliced variants in HCC, have been reported ( Table 1 ) [ 9 , 10 ].…”

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats

“…A 10% dimethyl sulfoxide (DMSO) stock for sorafenib tosylate and 0.9% sodium chloride for atoravastatin and metformin were used to prepare the drug solutions. Blood samples were collected before administration and after dosing at the following time points: 0.5, 1, 2, 3, 4, 5,6,7,8,10,12,24,30,48,72, and 96 h (for sorafenib); 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 6, and 12 h (for atorvastatin); and 0.083, 0.25, 0.5, 1, 1,5, 2, 4, 6, 8, 10, and 24 h (for metformin). The plasma was separated by centrifugation at 2880× g for 10 min at 4 • C and stored at −80 • C until drug analysis.…”

“…sodium hydroxide 3 67-56-1 sodium hydroxide microprills 5 1310-73-2 sorafenib 6 284461-73-0 sorafenib N-oxide 6 583840-03 rosuvastatin calcium 3 147098-20-2 ultrapure water (deionized, distilled, and filtered through Direct Q3 system) 4 7732-18-5 1 purchased from CHEMPUR (PiekaryŚląskie, Poland); 2 purchased from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA); 3 purchased from Sigma-Aldrich (Saint Louis, MO, USA); 4 purchased from Merck Millipore (Burlington, MA, USA); 5 purchased from POCH S.A. (Gliwice, Poland); 6 purchased from LGC (Teddington TW11 0LY, UK).…”

Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

“…Several studies indicated the importance of the member 22 of the solute carrier family (organic cation/anion transporter) in sorafenib resistance. SLC22A1 (OCT1) has been reported to be involved in the uptake of sorafenib, both in an animal model or human cells [53,54], even though a recent study showed opposing results [55]. Downregulation of OCT1 and OCT3 (SLC22A3) was observed in HCC [56,57] which was further associated with a poor survival in patients treated with sorafenib, independently from the clinical staging of the associated liver disease [58].…”