title: In vitro to in vivo comparison of the substrate characteristics of sorafenib tosylate toward P-glycoprotein.
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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Bayer Schering Pharma AG, Wuppertal, Germany. markjean.gnoth@bayerhealthcare.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Gnoth
authors.forename: S
authors.initials: S
authors.lastname: Sandmann
authors.forename: K
authors.initials: K
authors.lastname: Engel
authors.forename: M
authors.initials: M
authors.lastname: Radtke
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001557:Benzenesulfonates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D004077:Digoxin / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives; D010539:Permeability; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011725:Pyridines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000077157:Sorafenib; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D004077:Digoxin; D000077157:Sorafenib