Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters.
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Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD
Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters.
Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22.
- PubMed ID
- 19773380 [ View in PubMed]
- 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 micromol/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 transporter-related resistance mechanisms.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Sorafenib ATP-binding cassette sub-family G member 2 Protein Humans UnknownSubstrateInhibitorDetails Sorafenib Canalicular multispecific organic anion transporter 1 Protein Humans UnknownInhibitorDetails Sorafenib Multidrug resistance-associated protein 4 Protein Humans UnknownInhibitorDetails Sorafenib P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Sunitinib ATP-binding cassette sub-family G member 2 Protein Humans UnknownInhibitorDetails Sunitinib Canalicular multispecific organic anion transporter 1 Protein Humans UnknownInhibitorDetails Sunitinib Multidrug resistance-associated protein 4 Protein Humans UnknownInhibitorDetails Sunitinib P-glycoprotein 1 Protein Humans UnknownInhibitorDetails