Comprehensive analysis of endogenous compounds applicable to in vivo evaluation of drugs transporters

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659071
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: KUSUHARA Hiroyuki 東京大学, 薬学研究科(研究院), 教授 (00302612)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 薬物動態 / トランスポーター / 薬物間相互作用 / 個人間変動 / メタボローム / 代謝物

Research Abstract

The purpose of this study is to identify the endogenous probes that are applicable to in vivo evaluation of drug transporter activities in humans. The endogenous probes, the plasma or urinary excretion of which were associated with the transporter activities, were investigated in the biological samples from the healthy subjects who had been enrolled in the drug interaction studies. We could demonstrate that thiamine is a probe renal organic cation transporter (MATE), that 6beta-hydroxycortisol is a probe for renal organic anion transporter (OAT3). Their renal clearances were significantly reduced by the administration of inhibitors, showing their usefulness in the evaluation of drug-drug interactions involving these transporters.

Research Products

• [Journal Article] Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins (2014)
  • Author(s): Kato K, Mori H, Kito T, Yokochi M, Ito S, Inoue K, Yonezawa A, Katsura T, Kumagai Y, Yuasa H, Moriyama Y, Inui K, Kusuhara H, Sugiyama Y
  • Journal Title: Pharm Res Volume: 31 Pages: 136-147
  • Peer Reviewed
• [Journal Article] 6β-Hydroxycortisol is an endogenous probe for evaluation of drug-drug interactions involving a multispecific renal organic anion transporter, OAT3/SLC22A8, in healthy subjects (2014)
  • Author(s): Imamura Y, Tsuruya Y, Damme K, Heer D, Kumagai Y, Maeda K, Murayama N, Okudaira N, Kurihara A, Izumi T, Sugiyama Y, Kusuhara H
  • Journal Title: Drug Metab Dispos Volume: 42 Pages: 685-694
  • Peer Reviewed
• [Presentation] 薬物トランスポーターの発現・機能変動に伴い血漿中濃度・尿中排泄が変動する代謝物の探索 (2013)
  • Author(s): 楠原洋之
  • Organizer: 第86回日本生化学会
  • Place of Presentation: 横浜
  • Year and Date: 20130911-13
• [Presentation] Identification of major substrates of efflux transporters in vivo by metabolomics analysis (2013)
  • Author(s): 楠原洋之
  • Organizer: Gordon Research Conference Multi-Drug Efflux Systems
  • Place of Presentation: Ventura、USA
  • Year and Date: 20130317-22
• [Presentation] Metabolomic analysis of urine specimens after treatment with pyrimethamine, a potent inhibitor of multidrug and toxin extrusion (MATE) (2012)
  • Author(s): 加藤幸司, ほか
  • Organizer: 27^<th> JSSX Annual Meeting
  • Place of Presentation: 東京
  • Year and Date: 20121120-22
• [Presentation] Recent Developments in Drug-Transporter Research (2012)
  • Author(s): 楠原洋之
  • Organizer: 2012 AAPS Annual Meeting and Exposition
  • Place of Presentation: Chicago、USA
  • Year and Date: 20121014-18
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~molpk/