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

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

  • J Pharm Sci. 2017 Sep;106(9):2632-2641. doi: 10.1016/j.xphs.2017.04.064.
Ken-Ichi Fujita 1,  Yusuke Masuo 2,  Erina Yamazaki 2,  Toshiki Shibutani 2,  Yutaro Kubota 3,  Noritaka Nakamichi 2,  Yasutsuna Sasaki 4,  Yukio Kato 5
Affiliations

Affiliations

  • 1 Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
  • 2 Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kakuma-machi, Kanazawa University, Kanazawa 920-1192, Japan.
  • 3 Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
  • 4 Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
  • 5 Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kakuma-machi, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: ykato@p.kanazawa-u.ac.jp.
PMID: 28479358 DOI: 10.1016/j.xphs.2017.04.064
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/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.

Keywords

ABC transporters; P-glycoprotein; skin; tissue partition; transporters.

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