Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters

Abstract

Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents. Experimental Design: Uptake of [ 3 H]sorafenib or [ 3 H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters. Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9-and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls. Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporterrelated resistance mechanisms. (Clin Cancer Res 2009;15(19):6062-9) In recent years, eight orally administered, small-molecule tyrosine kinase inhibitors have been approved for the treatment of cancer in the United States. Among these, sorafenib and sunitinib are considered multikinase inhibitors because they inhibit multiple receptor and intracellular tyrosine kinases and exhibit antiangiogenic and antitumor activities (1-3). Sorafenib, an inhibitor of C-RAF, B-RAF, c-KIT, FLT-3, platelet-derived growth factor receptor β, and vascular endothelial growth factor receptors 1, 2, and 3, is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma (2). Sunitinib, an inhibitor of c-KIT, FLT-3, platelet-derived growth factor receptors α and β, and vascular endothelial growth factor 2, is approved for the treatment of advanced renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors (3). Sorafenib and sunitinib are being investigated for the treatment of other solid tumor malignancies (2, 3) and acute myelogenous leukemia (4,5).Studies have shown that tyrosine kinase inhibitors are substrates for and/or inhibit the function of various ATP-binding cassette (ABC) transporters, and these interactions may play an important role in modulating systemic pharmacokinetics of drugs, tissue and brain distribution, a...

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

“…The molecular mechanism underlying the sorafenib effect on ABCG2 efflux function is still under investigation. In addition to ABCG2, sorafenib blocks the function of other ABC transporters, including ABCB1, ABCC2, and ABCC4 (20,31). Hu and colleagues showed that sorafenib inhibits the ATPase activity of ABCC2 by directly interacting with this ABC transporter (31).…”

“…In addition to ABCG2, sorafenib blocks the function of other ABC transporters, including ABCB1, ABCC2, and ABCC4 (20,31). Hu and colleagues showed that sorafenib inhibits the ATPase activity of ABCC2 by directly interacting with this ABC transporter (31). Carloni and colleagues reported that sorafenib decreases the expression level of ABCC2 in some breast cancer cell Figure 6.…”

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

“…Therefore, its bioavailability is influenced by the activity of the excretory transporters ABCB1 and ABCG2 in the small-intestinal mucosa (Hu et al 2009;Gnoth et al 2010). In addition, sorafenib is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the small-intestinal mucosa or the liver, and it is also subjected to glucuronidation mediated by uridine diphosphate glucuronosyl transferase (UGT) 1A9 (Lathia et al 2006;Peer et al 2012;Filppula et al 2014).…”

Transport of six tyrosine kinase inhibitors: active or passive?

“…In our hands there is a clear difference between 4 °C and 37 °C, indicating an active transport. Hu et al [44] already reported that both sunitinib and sorafenib do not appear to rely on active transport to enter the cell. These drugs are also not a highaffinity substrate for the ABC-family transporters, which is in agreement with the data reported by this study.…”

“…Only cimetidine and desipramine decreased the relative accumulation of sorafenib. It is possible that all three hOCT should be inhibited to see an effect in relative accumulation of sorafenib, although Hu et al [44] reported that sorafenib does not appear to rely on active transport to enter the cell. Nevertheless, none of the used hOCT inhibitors are specific.…”