کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8514039 | 1556501 | 2017 | 55 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites
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کلمات کلیدی
ATP Binding Cassette Subfamily G Member 2P-gpCYP3A4ABCB1ATP Binding Cassette Subfamily B Member 1BcrpHFSABCG2LC-MS/MS - LC-MS / MSP-glycoprotein - P-گلیکوپروتئینTransporters - حمل و نقلABC transporters - حمل کننده ABCColorectal cancer - سرطان روده بزرگHand-Foot Syndrome - سندرم دست پاcytochrome P450 3A4 - سیتوکروم P450 3A4apparent permeability coefficient - ضریب نفوذپذیری ظاهریTissue partition - پارتیشن بافتPapp - پاپbreast cancer resistance protein - پروتئین مقاومت به سرطان سینهSkin - پوستCRC - کد افزونگی دورهای Liquid chromatography/tandem mass spectrometry - کروماتوگرافی مایع / طیف سنج جرم دو طرفه
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 9, September 2017, Pages 2632-2641
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 9, September 2017, Pages 2632-2641
نویسندگان
Ken-ichi Fujita, Yusuke Masuo, Erina Yamazaki, Toshiki Shibutani, Yutaro Kubota, Noritaka Nakamichi, Yasutsuna Sasaki, Yukio Kato,