Abstract 257: Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib

Abstract

The multikinase inhibitor sorafenib is approved for the treatment of advanced clear-cell renal and hepatocellular carcinomas, yet, patients’ survival is prolonged for only several months (Wilhelm et al., Mol Cancer Ther 2008). The understanding of this poor efficacy remains incomplete. One reason for treatment failure may be the high interindividual variability in pharmacokinetics of the orally-given sorafenib. Membrane transporters may contribute to pharmacokinetics of sorafenib and its metabolites as recently reported for the hepatic solute carrier (SLC) organic anion transporter family member 1B1 (OATP1B1) and OATP1B3 (Zimmerman et al, Clin Cancer Res 2013). In contrast, the role of organic cation transporter 1 (OCT1), which is also a major hepatic uptake transporter (Nies et al, Handb Exp Pharmacol 2011), for cellular uptake of sorafenib is controversial (Hu et al, Clin Cancer Res 2009; Swift et al, Drug Metab Dispos 2013; Herraez et al, Hepatology 2013). We therefore sought to comprehensively elucidate the impact of OCT1 on cellular sorafenib uptake by using a combination of different in vitro cell culture models and in vivo approaches involving experiments with Oct1 knockout (-/-) mice. Firstly, we analyzed cellular accumulation of radiolabeled sorafenib by the mammalian cell line HEK293 stably expressing OCT1. Despite overexpression of a functional OCT1 transporter, cellular uptake of neither sorafenib nor its active metabolite sorafenib N-oxide was increased. Next, we studied sorafenib and sorafenib N-oxide pharmacokinetics in mice with a homozygous genetic deletion of the Oct1 transporter. The deficiency of Oct1 had no influence on plasma and hepatic sorafenib and sorafenib N-oxide concentrations. Finally, we investigated sorafenib transport into the human hepatocellular carcinoma cell lines HepG2 and HuH7. Although neither OCT1 mRNA nor protein was detected, a considerable cellular accumulation of sorafenib was observed in both cell lines. Expression profiling of a panel of 55 relevant SLC drug uptake transporters identified several potential novel candidates mediating sorafenib accumulation. We conclude from these findings that cellular uptake of sorafenib and sorafenib N-oxide is independent of OCT1 and that other, as yet unidentified, transport mechanisms are responsible for cellular sorafenib uptake. Supported by the Robert Bosch Foundation, Stuttgart, Germany and the ICEPHA Grant Tübingen-Stuttgart, Germany. Citation Format: Claudia Neul, Sharyn D. Baker, Alex Sparreboom, Elke Schaeffeler, Stefan Laufer, Matthias Schwab, Anne T. Nies. Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 257.

Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential Effects on Bioavailability and Disposition of Tyrosine Kinase Inhibitors

“…Among the novel classes of anticancer drug development, small molecule tyrosine kinase inhibitors (TKIs) currently represent one of the most promising and rapidly expanding groups. Almost 25 TKIs (mostly in oral dosage form) have been already approved by international drug agencies, >130 are being evaluated in different phases of clinical trials, and many more are in various stages of development [22,23]. Most of TKIs are primarily metabolized by CYP3A4 and also interact with P-gp and/or Breast Cancer Resistance Protein (BCRP) where it serves as both substrates and inhibitors.…”

Impact of Promoter Polymorphisms on the Transcriptional Regulation of the Organic Cation Transporter OCT1 (SLC22A1)

“…This is now acknowledged as an important cause of variability in the pharmacokinetics and efficacy of drugs [17,18,19]. On the other hand, the tyrosine kinase inhibitors imatinib and sorafenib have been suggested to be affected by OCT1 polymorphisms, but the data is controversial with some detailed studies that were unable to confirm these drugs as substrates of OCT1 [20,21,22,23].…”