Prediction of interindividual differences of drug metabolism and pharmacokinetics using chimeric mice with humanized liver

• Project/Area Number: 23659053
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Hiroshima University
• Principal Investigator: OHTA Shigeru 広島大学, 大学院・医歯薬保健学研究院, 教授 (60160503)
• Co-Investigator(Kenkyū-buntansha): SANOH Seigo 広島大学, 大学院・医歯薬保健学研究院, 助教 (00552267)
• Research Collaborator: FUJIMOTO Mami 広島大学, 薬学部, 学生
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 薬学 / ヒト肝細胞移植キメラマウス / 肝細胞 / 薬物代謝酵素 / 遺伝多型 / 薬物動態 / 遺伝子多型

Research Abstract

Recently, intra-individual differences of drug metabolism and pharmacokinetics caused by the polymorphism of drug metabolic enzymes have been concerned in drug development. It is difficult to use drugs which show interindividual differencesbecause these result in changes of efficacy and safety. We used chimeric mice transplanted with human donor hepatocytes to examine whether chimeric mice reflect drug metabolism and pharmacokinetics of donors. In the results, it is possible to become useful models to predict interindividual differences of drug metabolism and pharmacokinetics.

Research Products

• [Journal Article] Prediction of human metabolism of thesedative-hypnotic zaleplonusing chimeric mice transplanted with human hepatocytes (2013)
  • Author(s): Tanoue C, Sugihara K, Uramaru N, Tayama Y,Watanabe Y, Horie T, Ohta S,Kitamura S
  • Journal Title: Xenobiotica
  • Peer Reviewed
• [Journal Article] 2,5-Dihydroxy-4-methoxybenzophenone: a novelmajorin vitro metabolite of benzophenone-3formed by rat and human liver microsomes (2013)
  • Author(s): Kamikyouden N, Sugihara K, Watanabe Y,Uramaru N, Murahashi T, Kuroyanagi M,Sanoh S, Ohta S, Kitamura S
  • Journal Title: Xenobiotica Volume: 43(6) Pages: 514-9
  • Peer Reviewed
• [Journal Article] Strain Difference of Oxidative Metabolism of the Sedative-Hypnotic Zaleplon by Aldehyde Oxidase and Cytochrome P450 in Vivo and in Vitro in Rats. (2013)
  • Author(s): Tanoue C, Sugihara K, Uramaru N, Watanabe Y, Tayama Y, Ohta S, Kitamura S.
  • Journal Title: Drug Metab Pharmacokinet. Volume: In press
  • NAID: 130004463299
  • Peer Reviewed
• [Journal Article] 2,5-Dihydroxy-4-methoxybenzophenone: a novel major in vitro metabolite of benzophenone-3 formed by rat and human liver microsomes (2013)
  • Author(s): Kamikyouden N., Sugihara K., Watanabe Y., Uramaru N., Murahashi T., Kuroyanagi M., Sanoh S., Ohta S., Kitamura S
  • Journal Title: Xenobiotica Volume: 43(6) Issue: 6 Pages: 514-519
  • DOI: 10.3109/00498254.2012.742217
  • Peer Reviewed
• [Journal Article] Predictability of metabolism of ibuprofen and naproxen using chimeric mice with human hepatocytes (2012)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y, Uramaru N, Ohshita H,Tateno C, Horie T, Kitamura S, Ohta S
  • Journal Title: Drug MetabDispos Volume: 40(12) Pages: 2267-72
  • Peer Reviewed
• [Journal Article] Prediction of in vivo hepatic clearance andhalf-life of drug candidates in human using chimeric mice with humanized liver (2012)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y, Ohshita H, Tateno C,Horie T, Kitamura S, Ohta S
  • Journal Title: Drug MetabDispos Volume: 40(2) Pages: 322-8
  • Peer Reviewed
• [Journal Article] Prediction ofhuman metabolism of FK3453 by aldehyde oxidase using chimeric mice transplantedwith human or rat hepatocytes (2012)
  • Author(s): Sanoh S, Nozaki K, Murai H, Terashita S, Teramura T, Ohta S
  • Journal Title: Drug MetabDispos Volume: 40(1) Pages: 76-82
  • Peer Reviewed
• [Journal Article] Predictability of metabolism of ibuprofen and naproxen using chimeric mice with human hepatocytes (2012)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y, Uramaru N, Ohshita H, Tateno C, Horie T, Kitamura S, Ohta S
  • Journal Title: Drug Metab Dispos Volume: 40(12) Issue: 12 Pages: 2267-72
  • DOI: 10.1124/dmd.112.047555
  • Peer Reviewed
• [Journal Article] Prediction of human metabolism of FK3453 by aldehyde oxidase usingchimeric mice transplanted with human or rathepatocytes (2012)
  • Author(s): Sanoh S, Nozaki K, Murai H, Terashita S, Teramura T, Ohta S
  • Journal Title: Drug Metabolism and Disposition Volume: 40(1) Issue: 1 Pages: 76-82
  • DOI: 10.1124/dmd.111.041954
  • Peer Reviewed
• [Journal Article] Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes (2012)
  • Author(s): Sanoh S., Horiguchi A., Sugihara K., Kotake Y., Tayama Y., Uramaru N., Ohshita H., Tateno C., Horie T., Kitamura S., Ohta S
  • Journal Title: Drug Metab Dispos Volume: 40(2) Issue: 2 Pages: 2267-2272
  • DOI: 10.1124/dmd.111.040923
  • Peer Reviewed
• [Presentation] ヒト肝細胞移植キメラマウスにおけるアロメトリックスケーリングを用いたヒト体内動態予測 (2013)
  • Author(s): 藤本真美, 佐能正剛,成富洋一,佐藤公也,河村章生,堀口 彩,杉原数美,立野知世,堀江 透,北村繁幸,太田 茂
  • Organizer: 日本薬学会 133 年会
  • Place of Presentation: 横浜
• [Presentation] ヒト肝細胞移植キメラマウスにおけるアロメトリックスケーリングを用いたヒト体内動態予測の検証 (2013)
  • Author(s): 藤本真美、佐能正剛、成富洋一、佐藤公也、河村章生、堀口 彩、杉原数美、立野知世、堀江 透、北村繁幸、太田 茂
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] ヒト肝細胞移植キメラマウスにおけるアロメトリックスケーリングを用いた血中動態予測性の検証 (2012)
  • Author(s): 藤本真美,佐能正剛,成富洋一,佐藤公也,河村章生,堀口 彩,杉原数美,立野知世,堀江 透,北村繁幸,太田 茂
  • Organizer: 日本薬物動態学会第27 年会
  • Place of Presentation: 東京
• [Presentation] Prediction of human pahemacokinetics by allometric scaling using chimeric mice with humanized liver (2012)
  • Author(s): Sanoh S, Naritomi Y, Sato K, Kawamura A, Horiguchi A, Sugihara K, Tateno C, HorieT, Kitamura S, Ohta S.
  • Organizer: 19thInternational Symposium on Microsomes and Drug Oxidations and 12thEuropean Regional International Society for the Study of Xenobiotics meeting
  • Place of Presentation: Noordwijkaan Zee (オランダ)
• [Presentation] ヒト肝細胞移植キメラマウスにおけるアロメトリックスケーリングを用いた血中動態予測性の検証 (2012)
  • Author(s): 藤本真美、佐能正剛、成富洋一、佐藤公也、河村章生、堀口 彩、杉原数美、立野知世、堀江 透、北村繁幸、太田 茂
  • 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（東京都）
• [Presentation] Prediction of human pharmacokinetics by allometric scaling using chimeric mice with humanized liver (2012)
  • Author(s): Seigo Sanoh, Yoichi NAritomi, Koya Sato, Akio Kawamura, Aya Horiguchi, KAzumi Sugihara, Chise Tateno, Toru Horie, Shigeyuki Kitamura, Shigeru Ohta
  • Organizer: 19th Ineternational Symposium on Microsomes and Drug Oxidations AND 12 th European Regional ISSX Meeting
  • Place of Presentation: Noordwijk aan Zee（The Netherlands）
• [Presentation] Prediction of PK parameters of human using human chimeric mice. (2011)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Tateno C, Horie T, Kitaura S, Ohta S.
  • Organizer: 17thInternational Society for the Study of Xenobiotics North American Meeting
  • Place of Presentation: Atlanta(アメリカ)
• [Presentation] Prediction of PK parameters of human using human chimeric mice (2011)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Tateno C, Horie T, Kitamura S, Ohta S
  • Organizer: 17th International Society for the Study of Xenobiotics North American Meeting
  • Place of Presentation: Atlanta, Georgia, USA