Mechanism identification of drug-induced rhabdomyolysis in patients with end-stage kidney disease and promotion of proper drug use

2013 Fiscal Year Final Research Report

• Project/Area Number: 23790607
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: TSUJIMOTO Masayuki 京都薬科大学, 薬学部, 講師 (90372739)
• Project Period (FY): 2011 – 2013
• Keywords: 末期腎不全 / 尿毒症物質 / 横紋筋融解症 / スタチン

Research Abstract

The objective in this study is to elucidate mechanism of drug-induced rhabdomyolysis in patients with end-stage kidney disease. In this study, we showed that uremic toxins, accumulated in patients with end-stage kidney disease, induce the functional decrease of metabolic enzyme (Cytochrome P450) with many drugs. In addition, we showed that uremic toxins increase drug-induced rhabdomyolysis by lipid-lowering agent (statins), and the increase results from the decrease in mevalonate and geranylgeranyl pyrophosphate. These results suggest that addition of mevalonate and geranylgeranyl pyrophosphate is useful for avoidance of statin-induced rhabdomyolysis in patients with end-stage kidney disease.

Research Products

• [Journal Article] Possibility of Decrease in CYP1A2 Function in Patients With End-Stage Renal Disease (2014)
  • Author(s): Masayuki Tsujimoto, Sari Sugimoto, Makiko Nagatomo, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Tetsuya Minegaki and Kohshi Nishiguchi
  • Journal Title: Ther Apher Dial Volume: 18 Pages: 174-180
  • DOI: 10.1111/1744-9987.12100
  • Peer Reviewed
• [Journal Article] Effects of Decreased Vitamin D and Accumulated Uremic Toxin on Human CYP3A4 Activity in Patients with End-Stage Renal Disease (2013)
  • Author(s): Masayuki Tsujimoto, Yui Nagano, Satomi Hosoda, Asuka Shiraishi, Ayaka Miyoshi, Shima Hiraoka, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Tetsuya Minegaki and Kohshi Nishiguchi
  • Journal Title: Toxins Volume: 5 Pages: 1475-1485
  • DOI: 10.3390/toxins5081475
  • Peer Reviewed
• [Journal Article] Influence of Serum in Hemodialysis Patients on the Expression of Intestinal and Hepatic Transporters for the Excretion of Pravastatin (2012)
  • Author(s): Masayuki Tsujimoto, Daisuke Hatozaki, Daisuke Shima, Hitoshi Yokota, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Tetsuya Minegaki, Kohshi Nishiguchi
  • Journal Title: Ther. Apher. Dial Volume: 16 Pages: 580-587
  • DOI: 10.1111/j.1744-9987.2012.01100.x
  • Peer Reviewed
• [Journal Article] 末期腎不全時に腎外クリアランスが変動する薬剤とその要因 (2012)
  • Author(s): 辻本雅之、峯垣哲也、西口工司
  • Journal Title: 日本腎臓病薬物療法学会誌 Volume: 1 Pages: 3-13
  • Peer Reviewed
• [Presentation] 末期腎不全患者血清を長期暴露した横紋筋細胞の作製とその機能評価 (2014)
  • Author(s): 筒井孝治、辻本雅之、内山仁、島田奈央美、新田彩佳、木村朱李、佐伯崇、結城絵理子、吉田拓弥、和泉智、山川智之、峯垣哲也、立木秀尚、西口工司
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-30
• [Presentation] ヒト横紋筋モデル細胞を用いたスタチンによる横紋筋障害への尿毒症物質の関与とその増強メカニズムの検討 (2014)
  • Author(s): 内山仁、辻本雅之、荻野仁未、小田智子、新本唯一、筒井孝治、島田奈央美、新田彩佳、吉田拓弥、和泉智、山川智之、峯垣哲也、立木秀尚、西口工司
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 20140328-30
• [Presentation] The Influence of Vitamin D and Uremic Toxins on Human CYP3A4 Activity and Expression (2013)
  • Author(s): Masayuki Tsujimoto, Yui Nagano, Satomi Hosoda, Asuka Shiraishi, Ayaka Miyoshi, Shima Hiraoka, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Tetsuya Minegaki and Kohshi Nishiguchi
  • Organizer: Annual Meeting American College of Clinical Pharmacology
  • Place of Presentation: Bethesda, MD, U.S.A
  • Year and Date: 20130922-24
• [Presentation] ヒト横紋筋モデル細胞における尿毒症物質によるスタチン毒性増強に及ぼすメバロン酸の影響 (2013)
  • Author(s): 内山仁、辻本雅之、荻野仁未、小田智子、新本唯一、島田奈央美、筒井孝治、新田彩佳、吉田拓弥、古久保拓、和泉智、山川智之、峯垣哲也、西口工司
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 20130328-30
• [Presentation] ヒト横紋筋モデル細胞におけるインドキシル硫酸によるスタチン系薬物の細胞毒性増強メカニズムの解明 (2012)
  • Author(s): 小田智子、辻本雅之、荻野仁未、新本唯一、吉田拓弥、古久保拓、和泉智、山川智之、峯垣哲也、西口工司
  • Organizer: 第22回日本医療薬学会年会
  • Place of Presentation: 新潟
  • Year and Date: 20121027-28
• [Presentation] CYP3A4発現量に及ぼす健常者血清と末期腎不全患者血清との相違性 (2012)
  • Author(s): 新本唯一、辻本雅之、白石明日香、永野唯、細田さとみ、島田奈央美、筒井孝治、新田彩佳、古久保拓、和泉智、山川智之、峯垣哲也、西口工司
  • Organizer: 第20回クリニカルファーマシーシンポジウムウム
  • Place of Presentation: 福岡
  • Year and Date: 20120714-15
• [Presentation] 末期腎不全患者血清による薬物代謝酵素CYP3A4の発現低下 (2012)
  • Author(s): 細田さとみ、辻本雅之、白石明日香、永野唯、島田奈央美、筒井孝治、新田彩佳、古久保拓、和泉智、山川智之、志摩大介、峯垣哲也、西口工司
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 20120328-31
• [Presentation] 末期腎不全患者に蓄積する尿毒症物質によるスタチン毒性の増強作用 (2011)
  • Author(s): 白石明日香,辻本雅之,永野唯,木村早希,細田さとみ,荻野仁未,小田智子,新本唯一,吉田拓弥,古久保拓,和泉智,山川智之
  • Organizer: 第32回日本臨床薬理学会年
  • Place of Presentation: 浜松
  • Year and Date: 20111201-03
• [Presentation] 末期腎不全患者血清による薬物代謝酵素CYP3A4の発現低下 (2011)
  • Author(s): 永野唯,辻本雅之,白石明日香,木村早希,細田さとみ,荻野仁未,小田智子,新本唯一,古久保拓,和泉智,山川智之,志摩大介,峯垣哲也,西口工司
  • Organizer: 第5回日本腎と薬剤研究会学術大会2011
  • Place of Presentation: 小倉
  • Year and Date: 20110917-18