Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2.
Regorafenib is a small molecule inhibitor of tyrosine kinases, and has been shown to improve the outcomes of patients with advanced colorectal cancer and advanced gastrointestinal stromal tumors. The transport profiles of regorafenib by various transporters were evaluated. HEK293/organic anion transporting polypeptide 1B1 (OATP1B1) cells exhibited increased drug sensitivity to regorafenib. Regorafenib inhibited the uptake of 3H-estrone sulfate by HEK293/OATP1B1 cells in a dose-dependent manner, but did not affect its elimination by P-glycoproteins. The concentration of regorafenib was significantly lower in LLC-PK1/multidrug resistance protein 2 (MRP2) cells than in LLC-PK1 cells treated with the MRP2 inhibitor, MK571. MK571 abolished the inhibitory effects of regorafenib on intracellular accumulation in LLC-PK1/MRP2 cells. The uptake of regorafenib was significantly higher in HEK293/OATP1B1 cells than in OATP1B1-mock cells. Transport kinetics values were estimated to be Km=15.9 µM and Vmax=1.24 nmol/mg/min. No significant difference was observed in regorafenib concentrations between HEK293/OATP1B3 and OATP1B3-mock cells. These results indicated that regorafenib is a substrate for MRP2 and OATP1B1, and also suggest that the substrate preference of regorafenib may implicate the pharmacokinetic profiles of regorafenib.
Laboratory of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University.
Hiroki
H
Ohya
Yoshihiko
Y
Shibayama
Jiro
J
Ogura
Katsuya
K
Narumi
Masaki
M
Kobayashi
Ken
K
Iseki
D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D018374:LLC-PK1 Cells; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D013552:Swine
D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D010671:Phenylurea Compounds; D011422:Propionates; D011725:Pyridines; D011804:Quinolines; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C559147:regorafenib; C059141:verlukast