Prediction of hepatic and renal clearance of drugs by using humanand animal-derived tissue samples and gene expression systems

• Project/Area Number: 19790119
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: MAEDA Kazuya The University of Tokyo, 大学院薬学系研究科, 助教 (00345258)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,580,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: 肝腎振り分け / トランスポーター / 肝細胞 / 腎スライス / 薬物間相互作用 / 薬物動態

Research Abstract

薬物の肝腎振り分けは、体内動態の特徴を知る上で重要であり、創薬の初期段階で予測できる方法論が望まれる。本研究では、ラットおよびヒト由来の肝細胞ならびに腎スライスを用いた取り込み実験の結果から、トランスポーター基質薬物の肝・腎クリアランスを定量的に予測する方法を構築し、さらに、肝細胞や胆管側膜ベシクルへの取り込みの阻害の情報を元にトランスポーターを介した薬物間相互作用を予測できることを実証した。

Research Products

• [Journal Article] Prediction of the hepatic and renal clearance of transporter substrates in rats using in vitro uptake experiments. (2009)
  • Author(s): Watanabe T, Maeda K, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y.
  • Journal Title: Drug Metab Dispos in press
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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, Inou e K, Ohta KY, Yuasa H, Kond o T, Nakayama H, Horita S, Kusuhara H, Sugiyama Y.
  • Journal Title: Drug Metab Dispos 37 Pages: 555-559
  • Peer Reviewed
• [Journal Article] Prediction of the hepatic and renal clearance of transporter substrates in rats using in vitro uptake experiments (2009)
  • Author(s): Watanabe T, Maeda K, Kondo T, Nakayama H, Horita S, Kusuhara H, Sugiyama, Y.
  • Journal Title: Drug Metab Dispos (In press)
  • Peer Reviewed
• [Journal Article] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. (2008)
  • Author(s): Kitamura S, Maeda K, Wang Y, Sugiyama Y
  • Journal Title: Drug Metab Dispos 36 Pages: 2014-2023
  • Peer Reviewed
• [Journal Article] Involvement of multiple transporters in the hepatobiliary tr ansport of rosuvastatin (2008)
  • Author(s): Kitamura S, Maeda K, Wang Y, Sugiyama Y
  • Journal Title: Drug Metab Dispos 36 Pages: 2014-2023
  • Peer Reviewed
• [Journal Article] Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. (2007)
  • Author(s): Yamada A, Maeda K, Kamiyama E, Sugiyama D, Kondo T, Shiroyanagi Y, Nakazawa H, Okano T, Adachi M, Schuetz JD, Adachi Y, Hu Z, Kusuhara H, Sugiyama Y.
  • Journal Title: Drug Metab Dispos 35 Pages: 2166-76
  • Peer Reviewed
• [Journal Article] Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective ant agonist of the angiotensin II AT1-receptor. (2007)
  • Author(s): Yamada A, et. al.
  • Journal Title: Drug Metab Dispos 35 Pages: 2166-2176
  • Peer Reviewed
• [Presentation] ヒト凍結肝細胞を利用した薬物の肝取り込み・胆汁排泄の予測法 (2009)
  • Author(s): 前田和哉
  • Organizer: シンポジウム「医薬品探索・開発のための細胞アッセイ技術」
  • Place of Presentation: 東京
  • Year and Date: 2009-01-08
• [Presentation] 遊離肝細胞を用いたin vitro 取り込み実験の結果に基づくin vivo肝クリアランスの予測の検討 (2008)
  • Author(s): 前田和哉, 渡辺友子, 渡辺貴夫, 出堀泰之, 楠原洋之, 杉山雄一
  • Organizer: 第16回肝病態生理研究会
  • Place of Presentation: 松山
  • Year and Date: 2008-06-04
• [Presentation] 遊離肝細胞を用いたin vitro取り込み実験の結果に基づくin vivo肝クリアランスの予測の検討 (2008)
  • Author(s): 前田和哉、渡辺友子、渡辺貴夫、出堀泰之、楠原洋之、杉山雄一
  • Organizer: 第16回肝病態生理研究会
  • Place of Presentation: 松山
  • Year and Date: 2008-06-04
• [Presentation] 遊離肝細胞、腎スライスを用いた医薬品の消失の肝腎振り分けのin vitro 予測法の検討 (2008)
  • Author(s): 渡辺友子, 前田和哉, 渡邉貴夫, 出掘泰之, 近藤恒徳, 楠原洋之, 杉山雄一
  • Organizer: 第15回HAB研究機構学術年会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-17
• [Presentation] 遊離肝細胞、腎スライスを用いた医薬品の消失の肝賢振り分けのinvitro予測法の検討 (2008)
  • Author(s): 渡辺友子、前田和哉、渡邉貴夫、出掘泰之、近藤恒徳、楠原洋之、杉山雄一
  • Organizer: 第15回HAB研究機構学術年会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-17
• [Presentation] Prediction of in vivo hepatic and renal clearance of transporter substrates from in vitro uptake clearance using isolated hepatocytes and kidney slices. (2008)
  • Author(s): Maeda K, Watanabe T, Watanabe T, Debori Y, Kusuhara H and Sugiyama Y.
  • Organizer: 2nd Asian-Pasific ISSX meeting
  • Place of Presentation: 上海, 中国
  • Year and Date: 2008-05-12
• [Presentation] Prediction of in vivo hepatic and renal clearance of transpcrter substrates from in vitro uptake clearance using isolated hepatocytes and kidney slices (2008)
  • Author(s): Maeda K, Watanabe T, Watanabe T, Debori Y, Kusuhara H and Sugiyama Y.
  • Organizer: 2^<nd> Asian-Pasific ISSX meeting
  • Place of Presentation: 上海、中国
  • Year and Date: 2008-05-12
• [Presentation] Physiologically based pharmacokinetic (PBPK) modeling for predicting transporter-mediated drug disposition in humans. (2007)
  • Author(s): Watanabe T, Kusuhara H, Maeda, K and Sugiyama Y.
  • Organizer: The 8th International ISSX Meeting
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-10
• [Presentation] Physiologically based pharmacokinetic (PBPK) modeling for predicting transporter-mediated drug disposition in humans (2007)
  • Author(s): Watanabe T, et. al.
  • Organizer: The 8th International ISSX Meeting
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-10
• [Presentation] トランスポーターを組み入れた生理学的薬物速度論モデリングによるヒトにおける薬物動態の予測と解析 (2007)
  • Author(s): 渡邉貴夫, 楠原洋之, 前田和哉, 杉山雄一
  • Organizer: 第15回肝病態生理研究会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-30
• [Book] 最新創薬学2007(分担執筆:肝取り込み・排泄の予測) (2007)
  • Author(s): 前田和哉
  • Publisher: メディカル・ドゥ
• [Book] John Wiley and Sons, Inc. (2007)
  • Author(s): Maeda K and Sugiyama Y.
  • Publisher: Drug Transporters (分担執筆:In vitro-in vivo scale-up of drug transport activities)
• [Book] Drug Transporters (分担執筆:In vitro-in vivo scale-up of drug transport activities) (2007)
  • Author(s): Maeda K, et. al.
  • Publisher: John Wiley and Sons, Inc.
• [Book] 最新創薬学2007(分担執筆:肝取り込み・排泄の予測) (2007)
  • Author(s): 前田 和哉
  • Publisher: メディカル・ドゥ