Strategy for protection of kidney injury based on functioal relation betwee renal specific stress response mechanisms and xenobiotic detoxication systems

• Project/Area Number: 17390158
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kumamoto University
• Principal Investigator: SAITO Hideyuki Kumamoto University, 医学部附属病院, 教授 (40225727)
• Co-Investigator(Kenkyū-buntansha): HAMADA Akinobu 熊本大学, 医学部附属病院, 准教授 (00322313) ; WATANABE Hiroshi 熊本大学, 薬学部, 講師 (70398220) ; 野々口 博史 熊本大学, 大学院・医学薬学研究部, 准教授 (30218341)
• Co-Investigator(Renkei-kenkyūsha): NONOGUCHI Hiroshi 熊本大学, 大学院・医学薬学研究部, 准教授 (30218341)
• Project Period (FY): 2005 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,750,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,950,000); Fiscal Year 2008: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2007: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2006: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥4,700,000 (Direct Cost: ¥4,700,000)
• Keywords: 急性腎障害 / 薬剤性腎障害 / 薬物トランスポータ / 抗癌薬 / 腎尿細管 / 腎障害 / 薬物排泄 / 尿毒症物質 / インドキシル硫酸 / シスプラチン

Research Abstract

虚血再灌流及び白金系抗癌薬誘発急性腎不全モデルラットにおいて、低酸素誘導因子の上昇に伴い腎近位尿細管上皮細胞に局在する有機アニオントランスポータおよび有機カチオントランスポータの発現・輸送機能が減少し、尿毒症物質やイオン型薬物の体内動態が著明に変動することを明らかにした。さらに、尿毒症物質の一つであるインドキシル硫酸がこれらトランスポータの発現変動並びに腎障害の進展に密接に関与することを突き止めた。

Research Products

• [Journal Article] Effects of oral administration of S-1 on the pharmacokinetics of SN-38, irinotecan active metabolite, in patients with advanced colorectal cancer (2009)
  • Author(s): Yokoo K, Hamada A, Tazoe K, Sasaki Y, Saito H.
  • Journal Title: Ther Drug Monit (in press)
  • NAID: 120002469601
  • Peer Reviewed
• [Journal Article] Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinib-resistance in K562 cells (2009)
  • Author(s): Hirayama C, Watanabe H, Nakashima R, Nanbu T, Hamada A, Kuniyasu A, Nakayama H, Kawaguchi T, Saito H.
  • Journal Title: Pharm Res. 25 Pages: 827-835
  • Peer Reviewed
• [Journal Article] Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats (2008)
  • Author(s): Morisaki T, Matsuzaki T, Yokoo K, Kusumoto M, Iwata K, Hamada A, Saito H
  • Journal Title: Pharm Res. 25 Pages: 2526-2533
  • NAID: 120002469602
  • Peer Reviewed
• [Journal Article] Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rOCT2 (Slc22a2)and rMATE1 (Slc47a1)in ischemia/reperfusioninduced acute kidney injury (2008)
  • Author(s): Matsuzaki T, Morisaki T, Sugimoto W, Yokoo K, Sato D, Nonoguchi H, Tomita K, Terada T, Inui K, Hamada A, Saito H.
  • Journal Title: Drug Metab Dispos 36 Pages: 649-654
  • Peer Reviewed
• [Journal Article] Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells (2008)
  • Author(s): Hira A, Watanabe H, Maeda Y, Yokoo K, Sanematsu E, Fujii J, Sasaki JI, Hamada A, Saito H.
  • Journal Title: Biochem Pharmacol 75 Pages: 973-980
  • Peer Reviewed
• [Journal Article] Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. (2008)
  • Author(s): Morisaki T, et al.
  • Journal Title: Pharmaceutical Research 25 Pages: 2526-2533
  • Peer Reviewed
• [Journal Article] Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rOCT2 (Slc22a2) and rMATE1 (Slc47al) in ischemia/reperfusion-induced acute kidney injury. (2008)
  • Author(s): Matsuzaki T, et al.
  • Journal Title: Drug Metabolism and Disposition 36 Pages: 649-654
  • Peer Reviewed
• [Journal Article] Role of P-glycoprotein in accumulation and cytotoxicity of amrubicin and amrubicinol in MDR1 gene-transfected LLC-PK1 cells and human A549 lung adenocarcinoma cells. (2008)
  • Author(s): Hira A, et al.
  • Journal Title: Biochemical Pharmacology 75 Pages: 973-980
  • Peer Reviewed
• [Journal Article] Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rOCT2 (Slc22a2) and rMATE1 (Slc47a1) in ischemia/reperfusion-induced actue kidney injury (2008)
  • Author(s): Matsuzaki T.
  • Journal Title: Drug Metabolism and Disposition 36(4) Pages: 649-654
  • Peer Reviewed
• [Journal Article] Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute renal failure (2007)
  • Author(s): Matsuzaki T, Watanabe H, Yoshitome K, Morisaki T, Hamada A, Nonoguchi H, Kohda Y, Tomita K, Inui K, Saito H
  • Journal Title: Kidney Int. 71 Pages: 539-547
  • Peer Reviewed
• [Journal Article] Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure (2007)
  • Author(s): Iwata K, Matsuzaki T, Watanabe H, Morisaki T, Ohmura T, Hamada A, SaitoH.
  • Journal Title: Pharm Res. 24 Pages: 662-671
  • Peer Reviewed
• [Journal Article] Involvement of Indoxyl Sulfate in Renal and Central Nervous System Toxicities During Cisplatin-Induced Acute Renal Failure (2007)
  • Author(s): Iwata K.
  • Journal Title: Pharmaceutical Research 24(4) Pages: 662-671
  • Peer Reviewed
• [Journal Article] Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute renal failure (2007)
  • Author(s): Matsuzaki T.
  • Journal Title: Kidney International 71(6) Pages: 539-547
  • Peer Reviewed
• [Journal Article] Downregulation of organic anion transporters in rat kidney under isehemia/reperfusion-induced acute renal failure. (2007)
  • Author(s): Matsuzaki T, et al.
  • Journal Title: Kindey Int. 71・6 Pages: 539-547
• [Journal Article] Involvement of indoxyl fulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure. (2007)
  • Author(s): Iwata K, et al.
  • Journal Title: Pharm.Res. (印刷中)
• [Journal Article] Down-regulation of V2 vasopressin receptor in dehydration : mechanisms and the role of renal prostaglandin synthesis. (2007)
  • Author(s): Machida K, et al.
  • Journal Title: Am.J.Physiol.Renal Physiol. (印刷中)
• [Journal Article] Effect of S-1 on pharmacokinetics of irinotecan in a patient with colorectal cancer. (2006)
  • Author(s): Yokoo K, et al.
  • Journal Title: Chin.Pharmacol.Ther. 80・4 Pages: 76-82
• [Journal Article] Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients. (2006)
  • Author(s): Matsunaga Y, et al.
  • Journal Title: Ther.Drug Monit. 28・1 Pages: 76-82
• [Journal Article] Chain length-dependent binding of fatty acid anions to human serum albumin studied by site-directed mutagenesis. (2006)
  • Author(s): Kragh-Hansen U, et al.
  • Journal Title: J.Mol.Bol. 363・3 Pages: 702-712
• [Journal Article] Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients. (2006)
  • Author(s): Matsunaga Y, et al.
  • Journal Title: Ther Drug Monit. 28・1 Pages: 76-82
• [Journal Article] Pharmacokinetic changes of irinotecan by intestinal alkalinization in an advanced colorectal cancer patient. (2005)
  • Author(s): Hamada A, et al.
  • Journal Title: Ther Drug Monit. 27・4 Pages: 536-538
• [Journal Article] Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer. (2005)
  • Author(s): Okamoto I, et al.
  • Journal Title: Cancer Chemother Pharmacol. 57・3 Pages: 282-288
• [Journal Article] Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder. (2005)
  • Author(s): Takimoto E, et al.
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. 289・5
• [Journal Article] Cytosolic Phospholipase A2 α Regulates Induction Of Brain Cyclooxygenase-2 In a Mouse Model of Inflammation. (2005)
  • Author(s): Sapirstein A, et al.
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. 288・6
• [Journal Article] Modulation of renal apical organic anion transporter 4 function by two PDZ domain-containing proteins. (2005)
  • Author(s): Miyazaki H, et al.
  • Journal Title: J Am Soc Nephrol. 16・12 Pages: 3498-3506
• [Presentation] Indoxyl sulfate is involved in the down-regulation of renal organic anion transporter OAT3 under ischemia/reperfusion-induced acute kidney injury (2008)
  • Author(s): Saito H. et.al.
  • Organizer: The 41^<st> Annual Meeting of American Society of Nephrology
  • Place of Presentation: フィラデルフィア
  • Year and Date: 2008-11-07
• [Presentation] Pathophysiological regulation of Slc22A organic anion transporters in cisplatin-induced acute kidney injury and uremia in rats (2008)
  • Author(s): Yokoo K. et.al.
  • Organizer: The 41^<st> Annual Meeting of American Society of Nephrology,
  • Place of Presentation: フィラデルフィア
  • Year and Date: 2008-11-07
• [Presentation] Regulation of renal organic anion transporters in cisplatin-induced acute kidney injury and uremia in rats. (2008)
  • Author(s): Saito H.
  • Organizer: 米国腎臓学会総会2008年会
  • Place of Presentation: ペンシルバニアコンベンションセンター
  • Year and Date: 2008-11-06
• [Presentation] シスプラチン誘発急性腎障害ラットにおける有機イオントランスポータ(Slc22A)ファミリーの発現・機能制御とファモチジン動態変動との関連 (2007)
  • Author(s): 森崎崇文ら
  • Organizer: 第30 回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2007-11-26
• [Presentation] Down-regulation of rat organic ion transporter (Slc22A) family members by ischemia/reperfusion-induced acute renal failure (2007)
  • Author(s): 齋藤 秀之
  • Organizer: 米国腎臓学会2007年会
  • Place of Presentation: Moscone Center (San Francisco、CA)
  • Year and Date: 2007-11-04
• [Presentation] Down-regulation of organic ion transporter (Slc22A)family members by ischemia/ reperfusion-induced acute renal failure (2007)
  • Author(s): Saito H. et.al.
  • Organizer: The 40^<th> Annual Meeting of American Society of Nephrology
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2007-11-01
• [Presentation] 虚血再灌流・急性腎不全ラットにおける有機アニオントランスポータrOAT1 及びrOAT3 の発現変動解析 (2006)
  • Author(s): 松崎尊信ら
  • Organizer: 第21 回日本薬物動態学会年会
  • Place of Presentation: 東京
  • Year and Date: 2006-11-30
• [Book] 腎機能を考えた安全な処方 (2006)
  • Author(s): 齋藤 秀之
  • Total Pages: 514
  • Publisher: 医薬ジャーナル社
• [Book] 医療薬学 (2005)
  • Author(s): 齋藤秀之
  • Total Pages: 419
  • Publisher: 廣川書店
• [Remarks]
  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/division/results.html