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Establishment of in vitro and in vivo models for human CES which promote rational development of ester-based prodrugs

Research Project

Project/Area Number 25293035
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Medical pharmacy
Research InstitutionChiba University

Principal Investigator

Chiba Kan  千葉大学, 薬学研究科(研究院), 教授 (40159033)

Co-Investigator(Kenkyū-buntansha) IMAI Teruko  熊本大学, 薬学部, 教授 (70176478)
HOSOKAWA Masakiyo  千葉科学大学, 薬学部, 教授 (70181500)
KOBAYASHI Kaoru  千葉大学, 大学院薬学研究院, 准教授 (30255864)
FURIHATA Tomomi  千葉大学, 大学院薬学研究院, 助教 (80401008)
Co-Investigator(Renkei-kenkyūsha) KAZUKI Yasuhiro  鳥取大学, 医学研究院, 准教授 (90403401)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2013: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Keywords薬物代謝 / 試験系 / プロドラッグ / CES / ヒト予測 / 評価 / 評価系 / 予測
Outline of Final Research Achievements

Carboxylesterase (CES) plays important roles in ester-type prodrug activation. It has been known that CES isoform expression profile of Caco-2 cells, widely-used human intestine model cells, differs from that of the human intestine. Therefore, we aimed to develop Caco-2 cells possessing human intestinal CES expression profile. Utilizing short-hairpin RNA against human CES1 mRNA and human CES2 expression retroviral system, CES2/CES1-KD/Caco-2 cells were developed. As seen in the human intestine, the CES2/CES1-KD/Caco-2 cells showed activity of CES2 but not CES1. Moreover, the cells showed the high transepithelial electric resistance value, indicating that the cells retained tight junction function. To summarize, we have successfully established a new Caco-2 cells that show the human intestine-like CES isoform expression profile. Thus, the CES2/CES1-KD/Caco-2 cells are expected to be a useful tool for ester-type prodrug development.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (8 results)

All 2016 2015 2014

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 1 results) Presentation (4 results)

  • [Journal Article] Synthesis and evaluation of atorvastatin esters as prodrugs metabolically activated by human carboxylesterases.2016

    • Author(s)
      Mizoi K, Takahashi M, Haba M, Hosokawa M.
    • Journal Title

      Bioorg Med Chem Lett.

      Volume: 26 Issue: 3 Pages: 921-923

    • DOI

      10.1016/j.bmcl.2015.12.069

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design of Fexofenadine Prodrugs Based on Tissue-Specific Esterase Activity and Their Dissimilar Recognition by P-Glycoprotein.2015

    • Author(s)
      Ohura K, Nakada Y, Kotani S, Imai T.
    • Journal Title

      J Pharm Sci.

      Volume: 104 Issue: 9 Pages: 3076-3083

    • DOI

      10.1002/jps.24467

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Systematic identification andcharacterization of carboxylesterases in cynomolgus macaques.2014

    • Author(s)
      Uno Y Uehara S, Hosokawa M, Imai T
    • Journal Title

      Drug Metab Dispos.

      Volume: 42 Issue: 12 Pages: 2002-2006

    • DOI

      10.1124/dmd.114.059972

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Perspective of humanized mouse models for assessing PK/PD and toxic profile of drug candidates in preclinical study.2014

    • Author(s)
      Kan Chiba
    • Journal Title

      Drug Metab Pharmacokinet.

      Volume: 29 Pages: 1-2

    • NAID

      130004463339

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] Dexamethasone mediate transcriptional regulation of carboxylesterase 1A1 gene in human fetal liver cells2014

    • Author(s)
      Hosokawa M, Hori T, Matsunaga T, Ohmori S.
    • Organizer
      19th North American ISSX/29thJSSX Meeting
    • Place of Presentation
      San Francisco、U.S.A.
    • Year and Date
      2014-10-19 – 2014-10-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Establishment of Caco-2 subclone with the low carboxylesterase activity for evaluation of human intestinal absorption of prodrug2014

    • Author(s)
      Ohura K, Sako S, Kurokawa K, Adachi Y, Ninomiya S, Imai T
    • Organizer
      19th North American ISSX/29thJSSX Meeting
    • Place of Presentation
      San Francisco, U.S.A.
    • Year and Date
      2014-10-19 – 2014-10-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] プロドラッグの小腸吸収予測のためのin vitro評価法の確立:カルボキシルエステラーゼ1低発現Caco-2サブクローンの細胞特性について2014

    • Author(s)
      迫沙央理、黒川敬介、大浦華代子、安達弥永、二宮真一、今井輝子
    • Organizer
      第134回日本薬学会年会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report
  • [Presentation] プロドラッグの吸収に及ぼす小腸粘膜代謝の影響2014

    • Author(s)
      田中啓一郎、今井輝子
    • Organizer
      第134回日本薬学会年会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report

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Published: 2013-05-21   Modified: 2019-07-29  

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