Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites

フォーマット:

論文

責任表示:

Fujita, Ken-ichi ; Masuo, Yusuke ; Yamazaki, Erina ; Shibutani, Toshiki ; Kubota, Yutaro ; Nakamichi, Noritaka ; Sasaki, Yasutsuna ; Kato, Yukio

言語:

英語

出版情報:

Elsevier B.V., 2017-09-01

著者名:

Fujita, Ken-ichi

Masuo, Yusuke

Yamazaki, Erina

Shibutani, Toshiki

Kubota, Yutaro

Nakamichi, Noritaka

Sasaki, Yasutsuna

Kato, Yukio

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掲載情報:

Journal of Pharmaceutical Sciences

ISSN:

0022-3549      

巻:

106

通号:

9

開始ページ:

2632

終了ページ:

2641

バージョン:

author

概要:

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/bcrp -/-; 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. © 2017 American Pharmacists Association®.<br />Embargo Period 12 months 続きを見る

URL:

http://hdl.handle.net/2297/48450