Abstract
Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(−/−) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(−/−) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(−/−) mice were 1.3- to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(−/−) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.
Footnotes
This study was supported by Bayer Schering Pharma AG, Wuppertal, Germany.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.032052.
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ABBREVIATIONS:
- VEGFR
- vascular endothelial growth factor receptor
- P-gp
- P-glycoprotein
- MDR/mdr
- multidrug resistance
- ABC
- ATP binding cassette
- WT
- wild-type
- TEER
- transepithelial electrical resistance
- DMSO
- dimethyl sulfoxide
- HPLC
- high-performance liquid chromatography
- B
- basolateral
- A
- apical
- KO
- knockout
- AUC
- area under the curve.
- Received January 5, 2010.
- Accepted April 22, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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