Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8514039 | Journal of Pharmaceutical Sciences | 2017 | 55 Pages |
Abstract
Regorafenib is a multikinase inhibitor orally administered to colorectal cancer patients, and is known to often exhibit dermal toxicity. The purpose of this study is to clarify possible involvement of P-glycoprotein and breast cancer resistance protein (BCRP) in the dermal accumulation of regorafenib and its active metabolites M-2 and M-5. Following intravenous administration in triple knockout (Abcb1a/1b/bcrpâ/â; TKO) and wild-type (WT) mice, delayed plasma clearance of M-2 and M-5, but not regorafenib, was observed in TKO mice compared to WT mice. Elacridar, an inhibitor of both transporters, also caused delayed clearance of M-2 and M-5, suggesting that these transporters are involved in their elimination. Skin-to-plasma concentration ratios of regorafenib, M-2, and M-5 were significantly higher in TKO mice than in WT mice. Elacridar increased skin-to-plasma and epidermis-to-plasma concentration ratios of regorafenib. Basal-to-apical transport of M-2 and M-5 was observed in LLC-PK1-Pgp and MDCKII/BCRP/PDZK1 cells, which was inhibited by elacridar and the BCRP inhibitor Ko143, respectively. The present findings thus indicate that P-glycoprotein and BCRP are involved in the accumulation of regorafenib and its active metabolites in the skin, by affecting either their systemic exposure or their plasma distribution in the circulating blood.
Keywords
ATP Binding Cassette Subfamily G Member 2P-gpCYP3A4ABCB1ATP Binding Cassette Subfamily B Member 1BcrpHFSABCG2LC-MS/MSP-glycoproteinTransportersABC transportersColorectal cancerHand-Foot Syndromecytochrome P450 3A4apparent permeability coefficientTissue partitionPappbreast cancer resistance proteinSkinCRCLiquid chromatography/tandem mass spectrometry
Related Topics
Health Sciences
Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Ken-ichi Fujita, Yusuke Masuo, Erina Yamazaki, Toshiki Shibutani, Yutaro Kubota, Noritaka Nakamichi, Yasutsuna Sasaki, Yukio Kato,