Expression and functions of drug transporters in renal tubules by kidney-specific oxidative stress and its role

• Project/Area Number: 20590143
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Mie University
• Principal Investigator: OKUDA Masahiro Mie University, 医学部附属病院, 教授 (70252426)
• Co-Investigator(Kenkyū-buntansha): IWAMOTO Takuya 三重大学, 医学附属病院, 准教授 (30447867) ; HIRAKU Yusuke 三重大学, 大学院・医学系研究科, 講師 (30324510)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2009: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2008: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: LLC-PK_1 / テトラエチルアンモニウム / 高グルコース / Trolox / 2011 / 10 / 02 / 虚血再灌流障害 / シメチジン / 腎分泌クリアランス / 肝虚血再灌流 / 酸化ストレス / rOCT2 / rMATE1 / 腎クリアランス / シクロスポリン / CYP3A / P-糖タンパク質 / OCT2 / LLC-PK1 / tetraethylammonium / L-buthionine sulfoximine / 多孔性フィルター / 脂質過酸化

Research Abstract

Effect of oxidative stress on the expression and function of organiccation transporter swere studied using cultured renal epithelial cell 1ine, LLC-PK_1, which retains organic cation transporters, and rats subjected to liver ischemia-reperfusion. Influx of cationic drugs across basolateral membranes into renal epithelial cells were decreased by oxidative stress by direct or indirect effect, and the involvement of decreased expression of organic cation transporter, OCT2, was suggested. These results provideuseful information for analysisof renal clearance of cationicdrugs in occasions of organdysfunction accompanying oxidative stress.

Research Products

• [Journal Article] Elevated systemic elimination of cimetidine in rats with acute biliary obstruction : the role of renal organic cation transporter OCT2. (2010)
  • Author(s): Kurata T, Muraki Y, Mizutani H, Iwamoto T, Okuda M
  • Journal Title: Drug Metab-Pharmacokinet 25 Pages: 328-334
  • NAID: 10027583140
  • Peer Reviewed
• [Journal Article] Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide. (2010)
  • Author(s): Mizutani H, Hiraku Y, Tada-Oikawa S, Murata M, Ikemura K, Twamoto T, Kagawa Y, Okuda M Kawanishi S
  • Journal Title: Cancer Sci 101 Pages: 2214-2219
  • NAID: 10027832563
  • Peer Reviewed
• [Journal Article] Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide. (2010)
  • Author(s): Mizutani, et al.
  • Journal Title: Cancer Sci Volume: 101 Pages: 2210-2219
  • Peer Reviewed
• [Journal Article] Elevated systemic elimination of cimetidine in rats with acute biliary obstruction : the role of renal organic cation transporter OCT2. (2010)
  • Author(s): Kurata, et al.
  • Journal Title: Drug Metab Pharmacokinet Volume: 25 Pages: 328-334
  • Peer Reviewed
• [Journal Article] Altered functions and expressions of drug transporters in liver, kidney and intestine in disorders of local and remote organs : possible role of oxidative stress in the pathogenesis. (2009)
  • Author(s): Ikemura K, Iwamoto T, Okuda M
  • Journal Title: Expert Opin Drug Metab Toxicol 5 Pages: 907-920
  • Peer Reviewed
• [Journal Article] The impact of total bilirubin on plasmamicafungin levels in living-donor liver transplantation recipients with severe liver dysfunction. (2009)
  • Author(s): Muraki Y, Iwamoto T, Kagawa Y, Sakurai H, Usui M, Tsaji S, Uemoto S, Okuda M
  • Journal Title: Biol Pharm Bull 32 Pages: 750-754
  • NAID: 110007160663
  • Peer Reviewed
• [Journal Article] Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats : The contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. (2009)
  • Author(s): Ikemura K, Urano K, Matsuda H, Mizutani H, Iwamoto T, Okuda M
  • Journal Title: J Pharmacol Exp Ther 328 Pages: 249-255
  • Peer Reviewed
• [Journal Article] The impact of total bilirubin on plasma micafungin levels in living-donor liver transplantation recipients with severe liver dysfunction (2009)
  • Author(s): Muraki, et al.
  • Journal Title: Biol Pharm Bull 32 Pages: 750-754
  • Peer Reviewed
• [Journal Article] Altered functions and expressions of drug transporters in liver, kidney and intestine in disorders of local and remote organs : possible role of oxidative stress in the pathogenesis (2009)
  • Author(s): Ikemura, et al.
  • Journal Title: Expert Opin Drug Metab Toxicol 5 Pages: 907-920
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 奥田
  • Journal Title: 薬物トランスポーター活用ライブラリー 第1章 (8) SLC22A1及びSLC22A2(羊土社 (東京)) Pages: 67-73
• [Journal Article] Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats : The contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. (2009)
  • Author(s): Ikemura, et al.
  • Journal Title: J Pharmacol Exp Ther 328 Pages: 249-255
  • Peer Reviewed
• [Journal Article] Inhibition of platelet aggregation by combined therapy with aspirin and cilostazol after off-pump coronary artery bypass surgery. (2008)
  • Author(s): Onoda K, Ohashi K, Hashimoto A, Okuda M, Shimono T, Nishikawa M, Shimpo H
  • Journal Title: Ann Thorac Cardiovasc Surg 14 Pages: 230-237
  • NAID: 10024307616
  • Peer Reviewed
• [Journal Article] Inhibition of platelet aggregation by combined therapy with aspirin and cilostazol after off-pump coronary artery bypass surgery. (2008)
  • Author(s): Onoda, et al.
  • Journal Title: Ann Thorac Cardiovasc Surg 14 Pages: 230-237
  • Peer Reviewed
• [Presentation] Altered function and expression of organic cation transporters, rOCTl and rOCT2, in acute cholestasis and their implications in the disposition and clearances of drugs. (2010)
  • Author(s): Kurata T, Muraki Y, Iwamoto T, Okuda M
  • 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: 東京都
  • Year and Date: 2010-11-08
• [Presentation] Altered function and expression of organic cation transporters, rOCT1 and rOCT2, in acute cholestasis and their implications in the disposition and clearances of drugs (2010)
  • Author(s): Kurata, et al.
  • 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: 東京都
  • Year and Date: 2010-11-08
• [Presentation] Pathophysiological role of chenodeoxycholic acid on hepatic disposition of metformin via organic cation transporter 1 in acute cholestasis. (2010)
  • Author(s): Kurata T, Muraki Y, Iwamoto T, Okuda M
  • Organizer: JSSX annual meeting 2010
  • Place of Presentation: さいたま市
  • Year and Date: 2010-10-09
• [Presentation] Pathophysiological Role of Chenodeoxycholic Acid on Hepatic Disposition of Metformin via Organic Cation Transporter 1 in Acute Cholestasis (2010)
  • Author(s): Kurata, et al.
  • Organizer: JSSX annual meeting 2010
  • Place of Presentation: さいたま市
  • Year and Date: 2010-10-09
• [Presentation] 肝虚血再灌流障害時におけるシメチジンの体内動態変動とその要因 (2010)
  • Author(s): 中川恵里加, 倉田朋彦, 池村健治, 岩本卓也, 奥田真弘
  • Organizer: 日本薬剤学会第25年会
  • Place of Presentation: 徳島市
  • Year and Date: 2010-05-12
• [Presentation] 塩酸イリノテカンとその代謝物の体内動態に及ぼす高尿酸血症の影響 (2010)
  • Author(s): 小田都紀子, 松田紘子, 倉田朋彦, 池村健治, 岩本卓也, 奥田真弘
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-03-30
• [Presentation] 塩酸イリノテカンとその代謝物の体内動態に及ぼす高尿酸血症の影響 (2010)
  • Author(s): 小田, ら
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2010-03-30
• [Presentation] Role of oxidative stress on decreased intestinal absorption of cyclosporine A by liver ischemia-reperfusion injury in rats. (2009)
  • Author(s): 池村健治, 水谷秀樹, 岩本卓也, 奥田真弘
  • Organizer: 24th JSSX Annual Meeting in Kyoto
  • Place of Presentation: 京都市
  • Year and Date: 2009-11-14
• [Presentation] Role of oxidative stress on decreased intestinal absorption of cyclosporine A by liver ischemia-reperfusion injury in rats (2009)
  • Author(s): Ikemura, et al.
  • Organizer: 24^<th> JSSX Annual Meeting in Kyoto
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2009-11-14
• [Presentation] 肝虚血再灌流障害時のCyclosporine Aのbioavailability低下における小腸CYP3A及びP-糖蛋白質の役割 (2008)
  • Author(s): 池村健治, 浦野公彦, 水谷秀樹, 岩本卓也, 奥田真弘
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌市
  • Year and Date: 2008-05-22
• [Presentation] 肝虚血再潅流障害時のCyclosporine A のbioavailability低下における小腸CYP3A及びP-糖蛋白質の役割 (2008)
  • Author(s): 池村, ら
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌市
  • Year and Date: 2008-05-22
• [Book] 薬物トランスポーター活用ライブラリー(第1章(8))(SLC22A1,SLC22A2) (2009)
  • Author(s): 奥田真弘
  • Publisher: 羊土社(東京)