Development of probe drugs for the evaluation of in vivo functions of drug transporters in humans

2010 Fiscal Year Self-evaluation Report

• Project/Area Number: 20249008
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: SUGIYAMA Yuichi The University of Tokyo, 大学院・薬学系研究科, 教授 (80090471)
• Project Period (FY): 2008 – 2011
• Keywords: 薬物トランスポーター / プローブ薬 / 体内動態 / 薬物間相互作用 / フェノタイピング / 律速段階

Research Abstract

本研究では、医薬品の体内動態に影響を与える因子の-つとしての薬物トランスポーターの機能をヒトin vivoにおいて定量的に推定するためのプローブ基質・阻害剤の探索、並びにそれらを用いることでヒト生体におけるトランスポーターの役割を予測する方法論の開発を目指したものである。これらの目的を達成するために、in vitro実験によるプローブ薬物の基質認識・阻害特性の検証、動物実験を介したプローブ薬物によるトランスポーター機能検証に関する検討、さらには、ヒト臨床試験を行い、プローブ薬物を用いたヒトin vivoにおけるトランスポーター機能の推定法の確立までを行うものである。

Research Products

• [Journal Article] Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving OAT3 in humans by in vitro uptake experiments. (2011)
  • Author(s): Watanabe T, Kusuhara H, Watanabe T, Debori Y, Maeda K, Kondo T, Nakayama H, Horita S, Ogilvie BW, Parkinson A, Hu Z, Sugiyama Y
  • Journal Title: Drug Metab Dispos in press
• [Journal Article] Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20-tetra norisocarbacyclin methyl ester for the evaluation of hepatobiliary transport. (2010)
  • Author(s): Takashima T, Nagata H, Nakae T, Cui Y, Wada Y, Kitamura S, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y.
  • Journal Title: J Pharmacol Exp Ther 335 Pages: 314-323
• [Journal Article] Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistance-associated protein (MRP) 2/MRP3 and OATPIBI/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4. (2009)
  • Author(s): Hirouchi M, Kusuhara H, Onuki R, Ogilvie BW, Parkinson A, Sugiyama Y.
  • Journal Title: Drug Metab Dispos 37 Pages: 2103-2111
• [Journal Article] The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine. (2009)
  • Author(s): Matsushima S, Maeda K, Inoue K, Ohta KY, Yuasa H, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y
  • Journal Title: Drug Metab Dispos 37 Pages: 555-559
• [Journal Article] The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling. (2008)
  • Author(s): Kato M, Shitara Y, Sato H, Yoshisue K, Hirano M, Ikeda T, Sugiyama Y
  • Journal Title: Drug Metab Dispos 25 Pages: 1891-1901
• [Presentation] IVIVE for hepatic and renal transporters (2010)
  • Author(s): Hiroyuki Kusuhara, Yuichi Sugiyama
  • Organizer: 2010 FIP PSWC/AAPS annual meeting and exposition
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2010-11-17
• [Presentation] Rate-determining process of a co-substrate of uptake transporter and metabolizing enzyme in the liver (2010)
  • Author(s): Yuichi Sugiyama
  • Organizer: MD02010
  • Place of Presentation: Beijing, China
  • Year and Date: 2010-05-17
• [Presentation] QUANTITATIVE PREDICTION OF THE CLEARANCE PATHWAYS OF TRANSPORTER SUBSTRATES FROM IN VITRO EXPERIMENTS (2009)
  • Author(s): Kazuya Maeda, Yuichi Sugiyama
  • Organizer: 7th Retrometabolism Based Drug Design and Targeting
  • Place of Presentation: Florida, USA
  • Year and Date: 2009-05-12
• [Presentation] Drug Transporters in the New Drug Discovery and Development (2009)
  • Author(s): Yuichi Sugiyama
  • Organizer: 3rd Asian Pacific Regional Meeting of ISSX
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2009-05-10
• [Presentation] Integration of In Vitro and In Vivo Data of Transporter Mediated Drug-drug Interaction and Pharmacogenomics (2008)
  • Author(s): Yuichi Sugiyama
  • Organizer: 2nd Asian-Pasific ISSX meeting
  • Place of Presentation: Shanghai, China
  • Year and Date: 2008-05-12