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Study of cationic drug efflux across the blood-retinal barrier

Research Project

Project/Area Number 26460193
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Medical pharmacy
Research InstitutionUniversity of Toyama

Principal Investigator

Kubo Yoshiyuki  富山大学, 大学院医学薬学研究部(薬学), 准教授 (20377427)

Co-Investigator(Kenkyū-buntansha) 赤沼 伸乙  富山大学, 大学院医学薬学研究部(薬学), 助教 (30467089)
Co-Investigator(Renkei-kenkyūsha) HOSOYA Ken-ichi  富山大学, 大学院医学薬学研究部(薬学), 教授 (70301033)
Nishi Tsuyoshi  大阪大学, 産業科学研究所, 准教授 (60403002)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords血液網膜関門 / トランスポーター / カチオン性薬物 / 神経保護薬 / 血液組織関門 / 血液脳関門 / インフラックス輸送 / エフラックス輸送
Outline of Final Research Achievements

In vivo transport study in rats suggested the facilitative transport systems for cationic compounds, such as clonidine, nicotine, riboflavin and L-ornithine at the blood-retinal barrier (BRB). In addition, in vitro transport study with TR-iBRB2 cells, an in vitro model cell line of the inner BRB, suggested the involvement of carrier-mediated process in these cationic drugs and compounds, showing the usefulness of clonidine transport system in systemic drug delivery to the retina. In vitro study of inhibition, vectorial transport and immunohistochemical analysis suggested the responsible contribution of cationic amino acid transporter 1 (CAT1/SLC7A1) to the blood-to-retina transport of L-ornithine at the inner and outer BRB. Knockdown study suggested the contribution of riboflavin transporter (RFVTs/SLC52A) to riboflavin transport at the inner BRB, and mRNA expression study supported that RFVT2 is dominant in the influx transport of riboflavin at the inner BRB.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (33 results)

All 2017 2016 2015 2014 Other

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Acknowledgement Compliant: 7 results,  Open Access: 4 results) Presentation (21 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results) Remarks (3 results)

  • [Journal Article] Blood-to-retina transport of riboflavin via RFVTs at the inner blood-retinal barrier2017

    • Author(s)
      Kubo Y, Yahata S, Miki S, Akanuma S, Hosoya K
    • Journal Title

      Drug Metab. Pharmacokinet

      Volume: 32 Issue: 1 Pages: 92

    • DOI

      10.1016/j.dmpk.2016.09.006

    • NAID

      210000188794

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Lysosomal Trapping Is Present in Retinal Capillary Endothelial Cells: Insight into Its Influence on Cationic Drug Transport at the Inner Blood–Retinal Barrier2016

    • Author(s)
      Kubo Y, Seko N, Usui T, Akanuma S, Hosoya K
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 8 Pages: 1319-1324

    • DOI

      10.1248/bpb.b16-00140

    • NAID

      130005254679

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Histamine elimination from the cerebrospinal fluid across the blood–cerebrospinal fluid barrier: involvement of plasma membrane monoamine transporter (PMAT/SLC29A4)2016

    • Author(s)
      Usui T, Nakazawa A, Okura T, Deguchi Y, Akanuma SI, Kubo Y, Hosoya K
    • Journal Title

      J Neurochem

      Volume: 139 Issue: 3 Pages: 408

    • DOI

      10.1111/jnc.13758

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Impact of SLC6A Transporters in Physiological Taurine Transport at the Blood–Retinal Barrier and in the Liver2016

    • Author(s)
      Kubo Y, Akanuma S, Hosoya K
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 12 Pages: 1903-1911

    • DOI

      10.1248/bpb.b16-00597

    • NAID

      130005171493

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional expression of nicotine influx transporter in A549 human alveolar epithelial cells2016

    • Author(s)
      Tega Y, Yuzurihara C, Kubo Y, Akanuma S, Ehrhardt C, Hosoya K
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: 31 Issue: 1 Pages: 99

    • DOI

      10.1016/j.dmpk.2015.11.006

    • NAID

      50014431248

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Carrier-mediated Transport of Cationic Drugs across the Blood-Tissue Barrier2015

    • Author(s)
      Kubo Y
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 135 Issue: 10 Pages: 1135-1140

    • DOI

      10.1248/yakushi.15-00181

    • NAID

      130005100628

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2015-10-01
    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Impact of cationic amino acid transporter 1 on blood-retinal barrier transport of L-ornithine2015

    • Author(s)
      Kubo Y, Obata A, Akanuma S, Hosoya K
    • Journal Title

      Invest Ophthalmol Vis Sci

      Volume: 56 Issue: 10 Pages: 5925

    • DOI

      10.1167/iovs.15-17398

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Carrier-Mediated Transport of Nicotine Across the Inner Blood-Retinal Barrier: Involvement of a Novel Organic Cation Transporter Driven by an Outward H<sup>+</sup> Gradient2015

    • Author(s)
      Tega Y, Kubo Y, Yuzurihara C, Akanuma S, Hosoya K
    • Journal Title

      J Pharm Sci

      Volume: 104 Issue: 9 Pages: 3069

    • DOI

      10.1002/jps.24453

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Involvement of carrier-mediated transport in the retinal uptake of clonidine at the inner blood-retinal barrier2014

    • Author(s)
      Kubo Y., Tsuchiyama A., Shimizu Y., Akanuma S., Hosoya K.
    • Journal Title

      Mol. Pharm.

      Volume: 11 Issue: 10 Pages: 3747

    • DOI

      10.1021/mp500516j

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 外側血液網膜関門riboflavin輸送機構における輸送担体の関与2017

    • Author(s)
      三木 智史、赤沼 伸乙、久保 義行、細谷 健一
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市 (宮城県)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] 血液網膜関門におけるカチオン性薬物・栄養物輸送機構2016

    • Author(s)
      久保 義行
    • Organizer
      第38回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      名古屋市 (愛知県)
    • Year and Date
      2016-11-17
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 血液組織関門における塩基性薬物吸排制御機構に関する研究2016

    • Author(s)
      久保 義行
    • Organizer
      日本薬物動態学会 第31回年会
    • Place of Presentation
      松本市 (長野県)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 血液網膜関門におけるSLC52A/RFVTを介したriboflavin輸送2016

    • Author(s)
      久保 義行、八幡 静香、三木 智史、赤沼 伸乙、細谷 健一
    • Organizer
      日本薬物動態学会 第31回年会
    • Place of Presentation
      松本市 (長野県)
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] 血液網膜関門を介した網膜からのポリアミン排出輸送機構の解明2016

    • Author(s)
      久保 義行、三浦 宏明、冨瀬 彩加、赤沼 伸乙、細谷 健一
    • Organizer
      日本脂質栄養学会
    • Place of Presentation
      秋田市 (秋田県)
    • Year and Date
      2016-09-16
    • Related Report
      2016 Annual Research Report
  • [Presentation] Impact of carrier-mediated transport of cationic neuroprotectants to the retina2016

    • Author(s)
      Yoshiyuki Kubo
    • Organizer
      The First International Symposium on Toyama-Asia-Africa Pharmaceutical Network
    • Place of Presentation
      Toyama, Japan
    • Year and Date
      2016-09-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 内側血液網膜関門における担体介在型putresine輸送機構の解明2016

    • Author(s)
      久保 義行、三浦 宏明、冨瀬 彩加、赤沼 伸乙、細谷 健一
    • Organizer
      日本薬学会第31年会
    • Place of Presentation
      岐阜市 (岐阜県)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] 内側血液網膜関門を介した網膜からのputrescine排出輸送機構の解明2016

    • Author(s)
      三浦宏明, 冨瀬彩加, 赤沼伸乙, 久保義行, 細谷健一
    • Organizer
      日本薬学会第136年会(横浜)
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-27
    • Related Report
      2015 Research-status Report
  • [Presentation] 血液脳脊髄液関門を介したspermine排出輸送特性2016

    • Author(s)
      島田浩和, 赤沼伸乙, 久保義行, 細谷健一
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-27
    • Related Report
      2015 Research-status Report
  • [Presentation] Nicotine生体膜輸送におけるH+/有機カチオン交換輸送体の関与2015

    • Author(s)
      手賀悠真,譲原千広,赤沼伸乙,久保義行,細谷健一
    • Organizer
      第37回生体膜と薬物相互作用シンポジウム
    • Place of Presentation
      熊本
    • Year and Date
      2015-11-19
    • Related Report
      2015 Research-status Report
  • [Presentation] 網膜へのriboflavin供給に対する血液網膜関門輸送機構の関与2015

    • Author(s)
      八幡静香,赤沼伸乙,久保義行,細谷健一
    • Organizer
      日本薬学会北陸支部第127回例会
    • Place of Presentation
      富山
    • Year and Date
      2015-11-15
    • Related Report
      2015 Research-status Report
  • [Presentation] 脳関門を介した脳からのspermine消失機構の解明2015

    • Author(s)
      島田浩和,赤沼伸乙,久保義行,細谷健一
    • Organizer
      日本薬学会北陸支部第127回例会
    • Place of Presentation
      富山
    • Year and Date
      2015-11-15
    • Related Report
      2015 Research-status Report
  • [Presentation] 血液網膜関門におけるnicotine輸送機構の解明2015

    • Author(s)
      譲原千広,手賀悠真,赤沼伸乙,久保義行,細谷健一
    • Organizer
      日本薬学会北陸支部第127回例会
    • Place of Presentation
      富山
    • Year and Date
      2015-11-15
    • Related Report
      2015 Research-status Report
  • [Presentation] 内側血液網膜関門を介した網膜から循環血液へのプトレシン輸送における輸送担体の関与2015

    • Author(s)
      三浦宏明, 冨瀬彩加, 赤沼伸乙, 久保義行, 細谷健一
    • Organizer
      日本薬物動態学会第30年会(東京)
    • Place of Presentation
      東京
    • Year and Date
      2015-11-13
    • Related Report
      2015 Research-status Report
  • [Presentation] 血液網膜関門riboflavin輸送におけるriboflavin transporters (RFVTs) の関与2015

    • Author(s)
      八幡静香,赤沼伸乙,久保義行, 細谷健一
    • Organizer
      日本薬学会第136年会(横浜)
    • Place of Presentation
      横浜
    • Year and Date
      2015-11-13
    • Related Report
      2015 Research-status Report
  • [Presentation] 血液脳脊髄液関門を介したヒスタミン排出輸送におけるPMATの関与2015

    • Author(s)
      臼井拓也,久保義行,赤沼伸乙,細谷健一
    • Organizer
      フォーラム富山「創薬」第41回研究会
    • Place of Presentation
      富山
    • Year and Date
      2015-05-28
    • Related Report
      2015 Research-status Report
  • [Presentation] 内側血液網膜関門を介したニコチン輸送におけるH+/有機カチオン対向輸送体の関与2015

    • Author(s)
      手賀悠真,譲原千広,赤沼伸乙,久保義行,細谷健一
    • Organizer
      フォーラム富山「創薬」第41回研究会
    • Place of Presentation
      富山
    • Year and Date
      2015-05-28
    • Related Report
      2015 Research-status Report
  • [Presentation] 血液網膜関門を介した1-Methyl-4-phenyl-pyridinium (MPP+) 排出輸送におけるPMAT (SLC29A4) の関与2015

    • Author(s)
      ○久保義行, 山本正和, 赤沼伸乙, 細谷健一
    • Organizer
      日本薬学会第135年
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-26
    • Related Report
      2014 Research-status Report
  • [Presentation] 血液網膜関門におけるカチオン性薬物輸送機構2014

    • Author(s)
      ○久保義行, 赤沼伸乙, 細谷健一
    • Organizer
      第36回生体膜と薬物相互作用シンポジウム
    • Place of Presentation
      徳島
    • Year and Date
      2014-11-21
    • Related Report
      2014 Research-status Report
  • [Presentation] 血液組織関門におけるカチオン性薬物輸送機構の解明2014

    • Author(s)
      ○久保義行
    • Organizer
      日本薬学会北陸支部会
    • Place of Presentation
      金沢
    • Year and Date
      2014-11-16
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] The blood-to-retina transport of clonidine at the inner blood-retinal barrier2014

    • Author(s)
      ○Kubo Y, Tsuchiyama A, Shimizu Y, Akanuma S, Hosoya K
    • Organizer
      19th North American Regional ISSX Meeting and 29th JSSX Annual Meeting
    • Place of Presentation
      San Francisco, U.S.A.
    • Year and Date
      2014-10-22
    • Related Report
      2014 Research-status Report
  • [Remarks] 富山大学 大学院医学薬学研究部 薬剤学研究室

    • URL

      http://www.pha.u-toyama.ac.jp/phaphzai/index-j.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 富山大学薬学部薬剤学研究室 研究概要

    • URL

      http://www.pha.u-toyama.ac.jp/phaphzai/reserch/index.html

    • Related Report
      2015 Research-status Report
  • [Remarks] 富山大学薬学部薬剤学研究室 研究業績

    • URL

      http://www.pha.u-toyama.ac.jp/phaphzai/reserch/publication.html

    • Related Report
      2015 Research-status Report

URL: 

Published: 2014-04-04   Modified: 2018-03-22  

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