Quantitative prediction of drug interactions based on the inhibition of hepatic uptake transporters

• Project/Area Number: 23590204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Musashino University
• Principal Investigator: ITO Kiyomi 武蔵野大学, 薬学研究所, 教授 (60232435)
• Co-Investigator(Kenkyū-buntansha): KUDO Toshiyuki 武蔵野大学, 薬学研究所, 助教 (10584815)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 薬物間相互作用 / 生理学的薬物速度論 / 定量的予測 / トランスポーター

Research Abstract

Drug-drug interactions involving the hepatic uptake transporters were analyzed based on a physiologically based pharmacokinetic model. As an example, the repaglinide concentration increase by co-administration of itraconazole and gemfibrozil was quantitatively explained by the inhibition of both hepatic uptake and metabolism of repaglinide. Application of the present model analysis to quantitative predictions of drug interactions involving hepatic uptake transporters is expected to facilitate the increased efficiency in drug development and avoidance of toxic interactions.

Research Products

• [Journal Article] Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes (2013)
  • Author(s): Kudo T, Hisaka A, Sugiyama Y, Ito K
  • Journal Title: Drug Metab Dispos Volume: 41(2) Pages: 362-371
  • Peer Reviewed
• [Journal Article] Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013)
  • Author(s): Godoy P, Hewitt NJ, Albrecht U他91名
  • Journal Title: Arch Toxicol Volume: 87(8) Pages: 1315-1530
  • Peer Reviewed
• [Journal Article] 薬物代謝酵素とトランスポーター (2013)
  • Author(s): 工藤敏之, 伊藤清美.
  • Journal Title: 呼吸 Volume: 32(5) Pages: 439-446
• [Journal Article] Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. (2013)
  • Author(s): P. Godoy, N. J. Hewitt, 他91名（48番目）
  • Journal Title: Arch. Toxicol. Volume: 87 Issue: 8 Pages: 1315-1530
  • DOI: 10.1007/s00204-013-1078-5
  • Peer Reviewed
• [Journal Article] 薬物代謝酵素とトランスポーター (2013)
  • Author(s): 工藤敏之、伊藤清美
  • Journal Title: 呼吸 Volume: 32 Pages: 439-446
• [Journal Article] Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes. (2013)
  • Author(s): Kudo T, Hisaka A, Sugiyama Y, Ito K.
  • Journal Title: Drug Metab Dispos. Volume: 41 Issue: 2 Pages: 362-371
  • DOI: 10.1124/dmd.112.049460
  • Peer Reviewed
• [Journal Article] 薬物代謝における薬物間相互作用の定量的予測 (2012)
  • Author(s): 伊藤清美
  • Journal Title: Drug Metab Pharmacokinetニュースレター Volume: 27(5) Pages: 8-11
• [Presentation] M&Sの基礎と解析事例 (2013)
  • Author(s): 伊藤清美
  • Organizer: 第34回日本臨床薬理学会学術総会
  • Place of Presentation: 東京国際フォーラム,東京
• [Presentation] 薬物相互作用のリスクを予測する (2013)
  • Author(s): 伊藤清美
  • Organizer: 第2回日本くすりと糖尿病学会学術集会
  • Place of Presentation: 星薬科大学,東京
• [Presentation] Analysis of the glibenclamide concentration increase by clarithromycin using a physiologically based pharmacokinetic model (2013)
  • Author(s): Kudo T, Shitara Y, Sugiyama Y, Ito K
  • Organizer: 日本薬物動態学会第28回年会
  • Place of Presentation: タワーホール船堀,東京
• [Presentation] Prediction of simultaneous inhibition of transporters and enzymes : Interaction between repaglinide and gemfibrozil/ itraconazole (2013)
  • Author(s): Ito K, Sugiyama Y
  • Organizer: 16th International Conference on Drug-Drug Interactions
  • Place of Presentation: Red Lion Hotel, Seattle, USA
• [Presentation] 糖尿病治療薬Glibenclamide，Nateglinide，Repaglinideの肝取り込みに占めるトランスポーターの寄与の解析 (2013)
  • Author(s): 橋爪研太, 青山晋輔, 前田和哉, 安達弥永, 伊藤清美, 杉山雄一
  • Organizer: 日本薬剤学会第28年会
  • Place of Presentation: 愛知県産業労働センター（愛知）
• [Presentation] Prediction of simultaneous inhibition of transporters and enzymes: Interaction between repaglinide and gemfibrozil/itraconazole. (2013)
  • Author(s): K. Ito, Y. Sugiyama
  • Organizer: 16th International Conference on Drug-Drug Interactions
  • Place of Presentation: Red Lion Hotel（Seattle, USA）
  • Invited
• [Presentation] Evaluation of drug interactions involving drug metabolism. (2013)
  • Author(s): K. Ito
  • Organizer: RIKEN The First International Conference of Sugiyama Laboratory
  • Place of Presentation: 日比谷コンベンションホール（東京）
  • Invited
• [Presentation] Analysis of the glibenclamide concentration increase by clarithromycin using a physiologically based pharmacokinetic model. (2013)
  • Author(s): T. Kudo, Y. Shitara, Y. Sugiyama, K. Ito
  • Organizer: 日本薬物動態学会第28回年会
  • Place of Presentation: タワーホール船堀（東京）
• [Presentation] 薬物相互作用のリスクを予測する (2013)
  • Author(s): 伊藤清美
  • Organizer: 第2回日本くすりと糖尿病学会学術集会
  • Place of Presentation: 星薬科大学（東京）
  • Invited
• [Presentation] M&Sの基礎と解析事例 (2013)
  • Author(s): 伊藤清美
  • Organizer: 第34回日本臨床薬理学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Invited
• [Presentation] Estimation of the contribution of CYP2C8 and CYP3A4 in the metabolism of repaglinide by human liver microsomes (2012)
  • Author(s): Kudo T, Komatsu S, Tanaka R, Oya Y, Hisaka A, Sugiyama Y, Ito K
  • Organizer: 日本薬物動態学会第27回年会
  • Place of Presentation: タワーホール船堀,東京
• [Presentation] Analysis of the glibenclamide concentration increase by clarithromycin based on the inhibition of hepatic uptake transporter and metabolic enzymes using a physiologically based pharmacokinetic model (2012)
  • Author(s): Kudo T, Sugiyama Y, Hisaka A, Ito K
  • Organizer: ISSX 18th North American Regional Meeting
  • Place of Presentation: Hilton Anatole Dallas Hotel, Texas, USA
• [Presentation] Analysis of the repaglinide concentration increase by gemfibrozil and itraconazole based on the inhibition of hepatic uptake transporter and metabolic enzymes (2012)
  • Author(s): Ito K, Kudo T, Sugiyama Y.
  • Organizer: 19th MDO and 12th European ISSX Meeting
  • Place of Presentation: Grand Huis ter Duin Hotel, Noordwijk aan Zee, the Netherlands
• [Presentation] 生理学的薬物速度論モデルを用いた薬物間相互作用の定量的予測方法に関する研究 (2012)
  • Author(s): 伊藤清美
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場,兵庫
• [Presentation] トランスポーターを介した薬物間相互作用の生理学的速度論モデルによる予測(5) : clarithromycin併用による血中glibenclamide濃度上昇の薬物動態学的解析 (2012)
  • Author(s): 工藤敏之, 杉山雄一, 伊藤清美
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場,兵庫
• [Presentation] Repaglinide代謝におけるCYP2C8及びCYP3A4の寄与率の測定 (2012)
  • Author(s): 大屋有加、工藤敏之、小松星菜、田中 諒、杉山雄一、伊藤清美
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] Clarithromycin併用による血中glibenclamide濃度上昇の薬物動態学的解析 (2012)
  • Author(s): 工藤敏之、杉山雄一、伊藤清美
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] 生理学的薬物速度論モデルを用いた薬物間相互作用の定量的予測方法に関する研究 (2012)
  • Author(s): 伊藤清美
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸国際会議場（兵庫）
  • Invited
• [Presentation] Analysis of the repaglinide concentration increase by gemfibrozil and itraconazole based on the inhibition of hepatic uptake transporter and metabolic enzymes. (2012)
  • Author(s): Kiyomi Ito, Toshiyuki Kudo, Yuichi Sugiyama
  • Organizer: 19th MDO and 12th European ISSX Meeting
  • Place of Presentation: Grand Hotel Huis ter Duin（Noordwijk aan Zee, the Netherlands）
• [Presentation] Analysis of the glibenclamide concentration increase by clarithromycin based on the inhibition of hepatic uptake transporter and metabolic enzymes using a physiologically based pharmacokinetic model. (2012)
  • Author(s): Toshiyuki Kudo, Yuichi Sugiyama, Akihiro Hisaka, Kiyomi Ito
  • Organizer: ISSX 18th North American Regional Meeting
  • Place of Presentation: Hilton Anatole Dallas Hotel（Texas, USA）
• [Presentation] Estimation of the contribution of CYP2C8 and CYP3A4 in the metabolism of repaglinide by human liver microsomes. (2012)
  • Author(s): Toshiyuki Kudo, Seina Komatsu, Ryo Tanaka, Yuka Oya, Akihiro Hisaka, Yuichi Sugiyama, Kiyomi Ito
  • Organizer: 27th JSSX Annual Meeting
  • Place of Presentation: タワーホール船堀（東京）
• [Presentation] レパグリニド代謝に関与するCYP分子種の寄与率の推定 (2012)
  • Author(s): 松原亜耶、堀田絵梨、工藤敏之、大屋有加、田中 諒、小松星菜、杉山雄一、伊藤清美
  • Organizer: 日本動物実験代替法学会第25回大会
  • Place of Presentation: 慶應義塾大学薬学部 芝共立キャンパス（東京）
• [Presentation] 消化管および肝臓での代謝における薬物間相互作用の予測 (2012)
  • Author(s): 伊藤清美
  • Organizer: 第332回CBI学会研究講演会
  • Place of Presentation: 東京大学弥生講堂一条ホール（東京）
  • Invited
• [Presentation] Analysis of the repaglinide concentration increase by itraconazole and gemfibrozil based on the inhibition of OATP1B1, CYP2C8 and CYP3A4 (2012)
  • Author(s): 工藤 敏之
  • Organizer: International Symposium on PPF Molecular Pharmacokinetics
  • Place of Presentation: 一橋記念講堂（東京都）
• [Presentation] Analysis of the repaglinide concentration increase by itraconazole and gemfibrozil considering the concentration profiles of both substrate and inhibitors (2011)
  • Author(s): Kudo T, Komatsu S, Tanaka R, Sugiyama Y, Ito K
  • Organizer: 日本薬物動態学会第26回年会
  • Place of Presentation: 広島国際会議場,広島
• [Presentation] 肝取り込みおよび肝代謝の阻害に基づくitraconazole, gemfibrozilとrepaglinideとの相互作用解析 (2011)
  • Author(s): 伊藤 清美
  • Organizer: 第19回肝病態生理研究会
  • Place of Presentation: ホテル日航東京（東京都）
• [Presentation] レパグリニドとイトラコナゾール、ゲムフィブロジルとの相互作用解析 (2011)
  • Author(s): 伊藤 清美
  • Organizer: 医療薬学フォーラム2011／第19回クリニカルファーマシーシンポジウム
  • Place of Presentation: 旭川市民文化会館（北海道）
• [Presentation] Analysis of the repaglinide concentration increase by itraconazole and gemfibrozil based on the inhibition of hepatic uptake transporter and metabolic enzymes (2011)
  • Author(s): 工藤 敏之
  • Organizer: BioMedical Transporters 2011
  • Place of Presentation: Congress Center (Grindelwald)
• [Presentation] Analysis of the repaglinide concentration increase by itraconazole and gemfibrozil considering the concentration profiles of both substrate and inhibitors (2011)
  • Author(s): 工藤 敏之
  • Organizer: 第26回日本薬物動態学会年会
  • Place of Presentation: 広島国際会議場（広島県）
• [Presentation] Prediction of drug-drug interactions involving metabolic inhibition.
  • Author(s): K. Ito
  • Organizer: Cyprotex Japanese ADME-Tox Symposium
  • Place of Presentation: 英国大使館（東京）
  • Invited
• [Book] 薬物相互作用ガイドラインの作成. GCPハンドブック第5版 (2014)
  • Author(s): 伊藤清美, 大野泰雄, 久米俊行, 斎藤嘉朗, 鈴木洋史, 永井尚美, 樋坂章博, 前田和哉
  • Publisher: 株式会社じほう
• [Book] GCPハンドブック 第5版 (2013)
  • Author(s): 伊藤清美, 大野泰雄, 久米俊行, 斎藤嘉朗, 鈴木洋史, 永井尚美, 樋坂章博, 前田和哉 他
  • Total Pages: 437
  • Publisher: 株式会社じほう
• [Book] 薬物間相互作用.疾患から見た臨床薬理学第3版 (2012)
  • Author(s): 伊藤清美, 杉山雄一
  • Publisher: 株式会社じほう
• [Book] 薬物トランスポーターについて教えてください.薬剤師のための糖尿病療養指導ガイド (2012)
  • Author(s): 工藤敏之, 伊藤清美, 杉山雄一
  • Publisher: 株式会社じほう
• [Book] 疾患から見た臨床薬理学 第3版 (2012)
  • Author(s): 伊藤清美、杉山雄一
  • Total Pages: 639
  • Publisher: 株式会社じほう
• [Book] 臨床薬理学 第3版 (2012)
  • Author(s): 伊藤 清美
  • Publisher: 医学書院
• [Book] 薬物代謝酵素とトランスポーター.臨床薬理学第3版 (2011)
  • Author(s): 伊藤清美, 杉山雄一
  • Publisher: 医学書院