Mechanism of drug resistance and its rational treatment based on pharmacodynamic analysis.

• Project/Area Number: 21590150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Gunma University
• Principal Investigator: YAMAMOTO Kojiro 群馬大学, 大学院・医学系研究科, 教授 (70174787)
• Co-Investigator(Kenkyū-buntansha): NAKAMURA Tomonori 群馬大学, 大学院・医学系研究科, 准教授 (30251151) ; NAKAMURA Katsunori 信州大学, 医学部附属病院, 准教授 (20361363)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 薬剤抵抗性 / ワルファリン / ビタミンK / VKORC1 / アザチオプリン / ITPA / 遺伝子多型 / ITPA遺伝子 / ビタミンKエポキシド還元酵素 / キサンチンオキシダーゼ / 遺伝子 / 薬剤反応性 / 臨床

Research Abstract

Vitamin K oxide reductase gene VKORC1 was important as a warfarin-resistant factor, while influence of CYP4F2, a vitamin K metabolism enzyme, was limited. Effect of thiopurine methyltransferase (TPMT) and inosine triphosphorus pyrophosphohydrolase (ITPA) was investigated in the systemic lupus erythematosus patients. Since treatment with azathioprine was provided at a low dose traditionally in Japan, azathioprine therapy is effective in the patients who had ITPA gene variant.

Research Products

• [Journal Article] CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subjects (2012)
  • Author(s): Katsunori Nakamura
  • Journal Title: J Clin Pharm Ther Volume: (in press) Issue: 4 Pages: 481-485
  • DOI: 10.1111/j.1365-2710.2011.01317.x
  • Peer Reviewed
• [Journal Article] CYP4F2 gene polymorphism as a contributor to warfar in maintenance dose in Japanese subjects (2011)
  • Author(s): Nakamura K, Obayashi K, Araki T, Aomori T, Fujita Y, Okada Y, Kurabayashi M, Hasegawa A, Ohmori S, Nakamura T, Yamamoto K
  • Journal Title: J. Pharmacy Ther Volume: (In press)
  • Peer Reviewed
• [Journal Article] Influence of CYP2C9 and VKORC1 polymorphisms on time to determine the warfarin maintenance dose (2011)
  • Author(s): Aomori T, Obayashi K, Fujita Y, Araki T, Nakamura K, Nakamura T, Kurabayashi M, Yamamoto K
  • Journal Title: Pharmazie Volume: 66 Pages: 222-225
  • Peer Reviewed
• [Journal Article] Influence of CYP2C9 and vitamin k oxide reductase complex (VKORC)1 polymorphisms on time to determine the warfarin maintenance dose (2011)
  • Author(s): Tohru Aomori
  • Journal Title: Pharmazie Volume: 66 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Influence of CYP2C9 and VKORC1 polymorphisms on time to determine the warfarin maintenance dose. (2011)
  • Author(s): Tohru Aomori
  • Journal Title: Die Pharmazie Volume: 66 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Inosine triphosphate pyrophosphatase 94C>A polymorphism : clinical implications for patients with systemic lupus erythematosus treated with azathioprine (2010)
  • Author(s): Yamamoto K, Okada Y, Nakamura K, Hiromura K, Nojima Y, Nakamura T
  • Journal Title: Exp Opin Drug Saf Volume: 9(3) Pages: 447-57
  • Peer Reviewed
• [Journal Article] Inosine triphosphate pyrophosphatase 94C>A polymorphism : clinical implications for patients with systemic lupus erythematosus treated with azathioprine. (2010)
  • Author(s): Koujirou Yamamoto
  • Journal Title: Expert Opinion in Drug Safety Volume: 9 Pages: 447-457
  • Peer Reviewed
• [Journal Article] Inosine triphosphate pyrophosphatase 94C>A polymorphism : clinical implications for patients with systemic lupus erythematosus treated with azathioprine. (2010)
  • Author(s): 山本康次郎, 岡田裕子, 中村智徳, et al.
  • Journal Title: Expert Opinion in Drug Safety (in press)
  • Peer Reviewed
• [Journal Article] Rapid SNP detection of the cytochrome P450 (CYP) 2C9 and the vitamin K oxide reductase (VKOR) gene for the warfarin dose adjustment by SMart-Amplification Process (2009)
  • Author(s): Aomori T, Yamamoto K, Oguchi-Katayama A, Kawai Y, Ishidao T, Mitani Y, Kogo Y, Lezhava A, Fujita Y, Obayashi K, Nakamura K, Kohnke H, Wadelius M, Ekstrom L, Skogastierna C, Rane A, Kurabayashi M, Murakami M, Cizdziel PE., Hayashizaki Y, Horiuchi R
  • Journal Title: Clin. Chem Volume: 55(4) Pages: 804-12
  • Peer Reviewed
• [Journal Article] Pro32Thr polymorphism of inosine triphosphate gene predicts efficacy of low-dose azathioprine for patients with systemic lupus erythematosus (2009)
  • Author(s): Okada Y, Nakamura K, Hiromura K, Nojima K, Horiuchi R, Yamamoto K
  • Journal Title: Clin. Pharmacol. Ther Volume: 85(5) Pages: 527-30
  • Peer Reviewed
• [Journal Article] 山本康次郎, 岡田裕子, 中村智徳 (2009)
  • Author(s): 山本康次郎, 岡田裕子, 中村智徳
  • Journal Title: 医薬ジャーナル Volume: 45(12) Pages: 3089-94
• [Journal Article] Pro32Thr polymorphism of inosine triphosphate gene predicts efficacy of low-dose azathioprine for patients with systemic lupus erythematosus. (2009)
  • Author(s): 岡田裕子, 中村智徳, Hiromura K, et al.
  • Journal Title: Clinical Pharmacology and Therapeutics 55 Pages: 527-530
  • Peer Reviewed
• [Journal Article] アザチオプリンの治療効果に対するITPA 94C>A遺伝子多型の影響 (2009)
  • Author(s): 山本康次郎、岡田裕子、中村智徳, 他
  • Journal Title: 医薬ジャーナル 45 Pages: 3089-3094
• [Journal Article] Sensitive and simple determination of vitamin K1 in human plasma by ultra-performance liquid chromatography coupled with a fluorescence detector
  • Author(s): Ohno, I, Araki T, Kawano M, Nakamura T, Yamamoto K
  • Journal Title: J Liq Chromatogr & Related Tech. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Sensitive and simple determination of vitamin K1 in human plasma by ultra-performance liquid chromatography coupled with a fluorescence detector
  • Author(s): Izumi Ohno
  • Journal Title: J Liq Chromatogr & Related Tech Volume: (印刷中)
  • Peer Reviewed
• [Presentation] Comparison of the VKOR inhibitory activity by S-and R-warfarin (2011)
  • Author(s): Kawano M, Araki T, Nakamura T, Yamamoto K
  • Organizer: 2nd Asian Federation for Pharmaceutical Sciences
  • Place of Presentation: Kuala Lumpur, Malaysia
  • Year and Date: 2011-12-09
• [Presentation] Comparison of the VKOR inhibitory activity by S-and R-warfarin (2011)
  • Author(s): Masashi Kawano
  • Organizer: 2nd Asian Federation for Pharmaceutical Science 2011
  • Place of Presentation: クアラルンプール(マレーシア)
  • Year and Date: 2011-12-09
• [Presentation] 肝ミクロソームを用いたSおよびRワルファリンによるVKOR阻害活性の比較検討 (2011)
  • Author(s): 川野雅嗣, 荒木拓也, 中村智徳, 山本康次郎
  • Organizer: 第55回日本薬学会関東支部大会
  • Place of Presentation: 東邦大学、船橋
  • Year and Date: 2011-10-08
• [Presentation] Effect of genetic polymorphisms on the efficacy of low-dose azathioprine therapy in patients with systemic lupus erythematosus (2011)
  • Author(s): Tohru Aomori
  • Organizer: 10th Congress of the European Association for Clinical Pharmacology and Therapeutics
  • Place of Presentation: ブダペスト(ハンガリー)
  • Year and Date: 2011-06-26
• [Presentation] Association of genotype, pharmacokinetics of vitamin Ks, and response of warfarin (2011)
  • Author(s): Takuya Araki, Masashi Kawano, Izumi Ohno, Tomonori Nakamura, Koujirou Yamamoto
  • Organizer: 第5回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 名古屋大学病院
• [Presentation] Effect of genetic polymorphisms on the efficacy of low-dose azathioprine therapy in patients with systemic lupus erythematosus (2011)
  • Author(s): Aomori T, Nagamine A, Takenaka M, Okada Y, Hiromura K, Nojima Y, Araki T, Nakamura T, Yamamoto K
  • Organizer: 10th Congress of the European Association for Clinical Pharmacology and Therapeutics
  • Place of Presentation: Budapest, Hungary
• [Presentation] Contribution of genetic polymorphisms to the efficacy of low-dose azathioprine therapy in Japanse patients with systemic lupus erythematosus. (2010)
  • Author(s): Ayumu Nagamine
  • Organizer: 第4回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-11-27
• [Presentation] ITPA遺伝子多型解析のSLE患者におけるアザチオプリン薬物療法への応用 (2010)
  • Author(s): 中村智徳
  • Organizer: 第20回日本医療薬学会
  • Place of Presentation: 千葉市
  • Year and Date: 2010-11-14
• [Presentation] The inpact of VKORC1 and CYP2C9 genetic polymorphisms on warfarin response in Indonesian patients (2010)
  • Author(s): Taofik Rusdiana
  • Organizer: 日本薬物動態学会第25回年会
  • Place of Presentation: さいたま市
  • Year and Date: 2010-10-07
• [Presentation] Contribution of genetic polymorphisms to the efficacy of low-dose azathioprine therapy in Japanese patients with systemic lupus erythematosus (2010)
  • Author(s): Ayumu Nagamine, Miki Takenaka, Tohru Aomori, Yuko Okada, Keiju Hiromura, Yoshihisa Nojima, Takuya Araki, Tomonori Nakamura, Koujirou Yamamoto
  • Organizer: 第4回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
• [Presentation] The Contribution of CYP3A5 and MDR1 (ABCB1) Polymorphisms on the pharmacokinetics of tacrolimus in patients with Rheumatoid arthritis and Lupus nephritis (2010)
  • Author(s): Ayano Ito, Yuko Okada, Keiju Hiromura, Yoshihisa Nojima, Takuya Araki, Tomonori Nakamura, Koujirou Yamamoto
  • Organizer: 第4回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
• [Presentation] ITPA遺伝子多型解析のSLE患者におけるアザチオプリン薬物療法への応用. シンポジウム20 病院薬剤師による薬物治療個別化への遺伝子情報の活用 (2010)
  • Author(s): 中村智徳
  • Organizer: 第20回日本医療薬学会年会
  • Place of Presentation: 千葉
• [Presentation] ワルファリン維持投与量に対するCYP4F2遺伝子多型の影響の検討 (2010)
  • Author(s): 中村克徳, 荒木拓也, 大林恭子, 川名純一, 倉林正彦, 中村智徳, 大森栄, 山本康次郎
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] Determination of genetic polymorphism of CYP2C9 and VKORC1 as a contributor of warfarin dose in Indonesian population. (2009)
  • Author(s): Taofik Rusdiana, 中村智徳, Takuya Araki, et al.
  • Organizer: 第24回日本薬物動態学会年会
  • Place of Presentation: 京都
  • Year and Date: 2009-11-28
• [Presentation] CYP4F2 gene polymorphism as a contributor of warfarin dose in Japanese (2009)
  • Author(s): Katsunori Nakamura, Kyoko Obayashi, Junichi Kawana, Hiroyasu Ogata, Kazuhiko Hanada, Masahiko Kurabayashi, Akira Hasegawa, Tomonori Nakamura, Koujirou Yamamoto
  • Organizer: 16th International Conference on Cytochrome P450
  • Place of Presentation: Nago, Okinawa, Japan
  • Year and Date: 2009-06-21
• [Presentation] CYP4F2 gene polymorphism as a contributor of warfarin dose in Japanese. (2009)
  • Author(s): 中村智徳, Kyoko Obayashi, Junichi Kawana, et al.
  • Organizer: 16th International Conference on Cytochrome P450
  • Place of Presentation: 名護(沖縄)
  • Year and Date: 2009-06-21
• [Presentation] Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in patients with rheumatoid arthritis and lupus nephritis (2009)
  • Author(s): Tomonori Nakamura, Yuko Okada, Keiju Hiromura, Yoshihisa Nojima, Katsunori Nakamura, Koujirou Yamamoto
  • Organizer: 3rd Asian Pacific Region ISSX Meeting
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2009-05-11
• [Presentation] Individualization of Azathioprine dose for patients with Systemic Lupus Erythematosus 38th European Society of Clinical Pharmacy (2009)
  • Author(s): Koujirou Yamamoto, Yuko Okada, Katsunori Nakamura, Tomonori Nakamura, Keiju Hiromura, Yoshihisa Nojima
  • Place of Presentation: Geneva, Switzerland
• [Presentation] Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in patients with rheumatoid arthritis and lupus nephritis (2009)
  • Author(s): Tomonori Nakamura, Yuko Okada, Keiju Hiromura, Yoshihisa Nojima, Katsunori Nakamura, Koujirou Yamamoto
  • Organizer: 30th American College of Clinical Pharmacy
  • Place of Presentation: Anaheim, CA, USA
• [Presentation] ワルファリン維持投与量決定までの期間に対する VKOR および CYP2C9 遺伝子型の影響 (2009)
  • Author(s): 青森達, 大林恭子, 中村克徳, 中村智徳, 倉林正彦, 三谷康正, 石田尾武文, 片山敦子, Alexander Lezhava, 林崎良英, 山本康次郎
  • Organizer: 第16回日本遺伝子診療学会
  • Place of Presentation: 札幌
• [Presentation] Individualization of Azathioprine dose for patients with Systemic Lupus Erythematosus. (2009)
  • Author(s): 山本康次郎, 岡田裕子, 中村智徳, 他
  • Organizer: 38th European Society of Clinical Pharmacy
  • Place of Presentation: ジュネーブ(スイス)
• [Remarks]
  • URL: http://clinpharmacol.dept.med.gunma-u.ac.jp/
• [Remarks]
  • URL: http://clinpharmacol.dept.med.gunma-u.ac.jp/
• [Remarks]
  • URL: http://clinpharmacol.dept.med.gunma-u.ac.jp/achievement2010.html
• [Remarks] 群馬大学大学院医学系研究科臨床薬理学分野
  • URL: http://clinpharmacol.dept.med.gunma-u.ac.jp/achievement2010.html