Development of the strategic pharmacotherapy using the genetic polymorphisms and the pharmacokinetics in the rheumatoid arthritis

• Project/Area Number: 25460192
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Gifu Pharmaceutical University (2014-2015); University of Shizuoka (2013)
• Principal Investigator: Hayashi Hideki 岐阜薬科大学, 薬学部, 准教授 (00419665)
• Co-Investigator(Kenkyū-buntansha): TODOROKI Kenichiro 静岡県立大学, 薬学部, 准教授 (70341451) ; YAMADA Hiroshi 静岡県立大学, 薬学部, 教授 (40265252) ; ITOH Kunihiko 静岡県立大学, 薬学部, 教授 (90221770)
• Research Collaborator: TAZOE Yui 静岡県立大学, 大学院, 大学院生 ; TSUBOI Seiji JA静岡厚生病院, 副院長 ; MATSUYAMA Taiji JA静岡厚生病院, 薬局長
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 関節リウマチ / メトトレキサート / 個別化医療 / 遺伝子解析 / 葉酸トランスポーター / TDM / 臨床薬理 / 血中薬物濃度 / 生物学的製剤 / トランスポーター

Outline of Final Research Achievements

Responsiveness to methotrexate (MTX), the "anchor drug" for treating rheumatoid arthritis (RA), varies among individual patients. In this study we investigated the effects of folate transporter gene expression levels on disease activity in the Japanese patients with RA who were undergoing MTX therapy. The mRNA expression levels of reduced folate carrier 1 (RFC1) in PBMCs from these patients were determined. There were large individual differences in RFC1 mRNA expression levels in both RA patients. RFC1 mRNA expression levels and RA disease activity scores were significantly negatively correlated, as disease activity scores were lower for patients with higher RFC1 mRNA expression levels. Thus, the clinical efficacy of MTX for Japanese RA patients was associated with the expression level of a folate transporter gene. We also attempted the therapeutic drug monitoring using measurement of the biological preparation in plasma and methotrexate and its active metabolite in red blood cells.

Research Products

• [Journal Article] Reduced folate carrier 1 gene expression levels are correlated with methotrexate efficacy in Japanese patients with rheumatoid arthritis. (2015)
  • Author(s): Tazoe Y, Hayashi H, Tsuboi S, Shioura T, Matsuyama T, Yamada H, Hirai K, Tsuji D, Inoue K, Sugiyama T, Itoh K
  • Journal Title: Drug Metab. Pharmacokinet. Volume: in press Issue: 3 Pages: 227-230
  • DOI: 10.1016/j.dmpk.2015.02.001
  • NAID: 50014429955
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 薬物動態インフォメーションを活用した臨床薬理研究の動向と新展開 関節リウマチ治療薬メトトレキサートの薬効に影響する葉酸トランスポーターの遺伝子多型 (2015)
  • Author(s): 林秀樹, 田添唯, 坪井声示, 松山耐至, 杉山正, 伊藤邦彦
  • Organizer: 日本薬物動態学会第30回年会
  • Place of Presentation: タワーホール船堀(東京）
  • Year and Date: 2015-11-12
• [Presentation] 抗体医薬のTDM ―関節リウマチ患者における検討― (2014)
  • Author(s): 大鹿雄美，山宮 翔，田添 唯，林 秀樹，松山耐至，坪井声示，轟木堅一郎，井上和幸，辻 大樹，山田 浩，豊岡利正，伊藤邦彦
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本県熊本市