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薬剤性移植肝障害発現の分子機構解明

Research Project

Project/Area Number 21689017
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Applied pharmacology
Research InstitutionKyoto University

Principal Investigator

増田 智先  京都大学, 医学(系)研究科(研究院), 講師 (90303825)

Project Period (FY) 2009 – 2012
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2011: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2010: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2009: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Keywordsトランスポータ / 代謝酵素 / MDR1 / マイクロアレイ / タクロリムス / 薬物相互作用 / 薬物感受性 / 免疫抑制薬 / トーンスポータ
Research Abstract

肝移植患者において、一般的な肝機能マーカーであるトランスアミナーゼ(AST、ALT)や総ビリルビン(T-Bil)の上昇を認めないSubclinicalな拒絶反応の半数は、引き続きこれらマーカーの上昇を伴うClinicalな拒絶反応へと進行する。現状では、肝生検を用いた病理診断によって拒絶反応を診断するが、C型肝炎(HCV)ウィルスに感染した患者では肝炎再燃の病理像との区別が困難であること、薬剤性肝障害の可能性も否定できない等の問題点に対して、「移植肝障害」の原因究明に繋がる分子生物学的指標の同定を到達目標として研究を進めた。
平成22年度では、初年度で得られた成果について研究を進め、肝臓移植後の胆汁中代謝物の濃度が移植肝における拒絶反応をはじめとする障害を反映しうることを明らかにした。特に、胆汁中のタンパク質約50種類を調べたところ、一部の炎症関連タンパク質の胆汁中濃度は,胆汁中タクロリムス代謝物濃度と良好な負の相関関係を示し、移植肝の解毒能を反映するバイオマーカーとして有望なことが強く示唆された。今後、前向き検討を進めることによって、移植肝障害のバイオマーカーとして臨床活用可能かどうかを明らかにしたいと考える。

Report

(2 results)
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (17 results)

All 2011 2010 2009

All Journal Article (11 results) (of which Peer Reviewed: 10 results) Presentation (6 results)

  • [Journal Article] Tacrolimus Therapy as an Alternative to Thiopurines for Maintaining Remission in Patients With Refractory Ulcerative Colitis2011

    • Author(s)
      Yamamoto S
    • Journal Title

      J Clin Gastroenterol

      Volume: (In press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 高度医療における医薬品情報提供と薬剤師の役割2010

    • Author(s)
      増田智先
    • Journal Title

      薬事

      Volume: 52 Pages: 2019-2024

    • Related Report
      2010 Annual Research Report
  • [Journal Article] Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis2010

    • Author(s)
      Yoshino T
    • Journal Title

      J Gastroenterol Hepatol

      Volume: 16 Pages: 2022-2033

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficacy and safety of infliximab as rescue therapy for ulcerative colitis refractory to tacrolimus2010

    • Author(s)
      Yamamoto S
    • Journal Title

      J Gastroenterol Hepatol

      Volume: 25 Pages: 886-891

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients2010

    • Author(s)
      Toyama K
    • Journal Title

      Pharmacogenet Genomics

      Volume: 20 Pages: 135-138

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Time-saving multiplex detection of single nucleotide polymorphisms by ultrasensitive DNA microarray2010

    • Author(s)
      Ichikawa M
    • Journal Title

      J Biochem

      Volume: 148 Pages: 557-563

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Larger dosage required for everolimus than sirolimus to maintain same blood concentration in two pancreatic islet transplant patients with tacrolimus.2009

    • Author(s)
      Sato E
    • Journal Title

      Drug Metab Pharmacokinet 24

      Pages: 175-179

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Absence of influence of concomitant administration of rabeprazole on the pharmacokinetics of tacrolimus in adult living-donor liver transplant patients : a case-control study2009

    • Author(s)
      Hosohata K
    • Journal Title

      Drug Metab Pharmacokinet 24

      Pages: 458-463

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients2009

    • Author(s)
      Hosohata K
    • Journal Title

      Pharm Res 26

      Pages: 1590-1595

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of intestinal CYP2C19 genotypes on the interaction between tacrolimus and omeprazole, but not lansoprazole, in adult living-donor liver transplant patients2009

    • Author(s)
      Hosohata K
    • Journal Title

      Drug Metab Dispos 37

      Pages: 821-826

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Risk factors for recurrence of primary sclerosing cholangitis after living donor liver transplantation : a single center experience2009

    • Author(s)
      Egawa H
    • Journal Title

      Dig Dis Sci 54

      Pages: 1347-1354

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] 慢性拒絶の診断後にシロリムスが奏功した小児肝移植症例について2011

    • Author(s)
      増田智先
    • Organizer
      12回肝移植術後管理検討会
    • Place of Presentation
      メルパルク京都、京都市(招待講演)
    • Year and Date
      2011-01-29
    • Related Report
      2010 Annual Research Report
  • [Presentation] Effectiveness of sirolimus therapy in combination with cyclosporine against chronic rejection in a pediatric liver transplant patient2011

    • Author(s)
      Satohiro Masuda
    • Organizer
      第112回米国臨床薬理学会年会(ASCPT)
    • Place of Presentation
      Hyatt Regency Dallas、Dallas、USA
    • Related Report
      2010 Annual Research Report
  • [Presentation] 免疫抑制剤の投与設計2010

    • Author(s)
      増田智先
    • Organizer
      第17回薬と医療シンポジウム「個別化医療の基礎と臨床」
    • Place of Presentation
      常翔学園OITホール,大阪市(招待講演)
    • Year and Date
      2010-08-21
    • Related Report
      2010 Annual Research Report
  • [Presentation] 近位尿細管トランスクリプトームに基づく薬剤性尿中バイオマーカーの探索2010

    • Author(s)
      増田智先
    • Organizer
      第31回臨床薬理学会年会
    • Place of Presentation
      国立京都国際会館、京都市(招待講演)
    • Related Report
      2010 Annual Research Report
  • [Presentation] mTOR阻害薬の腎への作用2010

    • Author(s)
      増田智先
    • Organizer
      第53回日本腎臓学会学術総会
    • Place of Presentation
      神戸国際会議場、神戸市(招待講演)
    • Related Report
      2010 Annual Research Report
  • [Presentation] 薬剤性腎障害の発現機構解明とバイオマーカーの探索2010

    • Author(s)
      増田智先
    • Organizer
      HAB研究機構学術年会
    • Place of Presentation
      昭和大学上条行動、東京都(招待講演)
    • Related Report
      2010 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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