title: Lack of Contribution of Multidrug Resistance-associated Protein and Organic Anion-transporting Polypeptide to Pharmacokinetics of Regorafenib, a Novel Multi-Kinase Inhibitor, in Rats.
abstract: We investigated whether hepatic multidrug resistance-associated protein 2 (ABCC2) is involved in the hepatobiliary excretion of regorafenib, a novel multi-kinase inhibitor, using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) lacking the efflux transporter ABCC2. The involvement of organic anion-transporting polypeptide 1 (OATP1; OATP in humans) and OATP2 in the hepatic uptake of regorafenib and their protein levels in the liver were also investigated in the two rat groups. When regorafenib (5 mg/kg) was administered intravenously, the plasma concentrations of regorafenib were higher in EHBR than those in SD rats. However, the slope of the plasma concentration-time curves was the same for the two groups. Although the apparent biliary clearance of regorafenib in EHBR was lower than that of SD rats, no significant difference in the biliary excretion rate was observed between them, suggesting that regorafenib is not a substrate for ABCC2 and is not excreted into bile by ABCC2. It was also found that the contribution of biliary excretion to the systemic elimination of regorafenib is small. The protein-binding profiles of regorafenib were found to be linear in both rat groups. The binding potency, which was very high in both rat groups (>99.5%), was significantly higher in EHBR than that in SD rats. No significant differences in the plasma concentrations of unbound regorafenib were observed between the two rat groups, suggesting that the differences observed in the pharmacokinetic behaviors of regorafenib between the two rat groups were due to differences in protein-binding. When the protein levels of hepatic OATP1 and OATP2 were measured by immunoblot analysis, the expression of both transporters in EHBR was less than 40% of that in SD rats. The present results suggest that regorafenib is not a substrate for OATP1 and OATP2. These findings suggest the possibility that ABCC2-mediated hepatobiliary excretion and OATP1/OATP2-mediated hepatic uptake do not play important roles in the disposition of regorafenib.
authors.affiliation: Department of Hospital Pharmacy, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hotta
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Higashi-ku, Nagoya, Aichi, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.affiliation: Department of Medicine, Aichi Gakuin University School of Pharmacy, Chikusa-ku, Nagoya, Aichi, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tatsumi
authors.affiliation: Department of Hospital Pharmacy, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Ikuto
authors.initials: I
authors.lastname: Tsukiyama
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Higashi-ku, Nagoya, Aichi, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sugiura
authors.affiliation: Faculty of Pharmacy, Meijo University, Tenpaku-ku, Nagoya, Aichi, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Hospital Pharmacy, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Hospital Pharmacy, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan takahase@aichi-med-u.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000077210:Sunitinib
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D007211:Indoles; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; C421102:Slco1a1 protein, rat; C503597:Slco1a4 protein, rat; C559147:regorafenib; D000077210:Sunitinib
keywords: Regorafenib; biliary excretion; disposition; hepatic uptake; multidrug resistance-associated protein; organic anion-transporting polypeptide; protein-binding