Novel strategy for development of suppressive drugs for kidney disease based on inhibition of metabolic production of uremic toxins

• Project/Area Number: 21390048
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: SAITO Hideyuki 熊本大学, 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)
• Co-Investigator(Renkei-kenkyūsha): NONOGUCHI Hiroshi 兵庫医科大学, 医学部, 准教授 (30218341) ; MASUDA Satohiro 京都大学, 医学部附属病院, 講師 (90303825)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2011: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2010: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 急性腎障害 / 慢性腎不全 / 尿毒症物質 / 腎尿細管 / 腎障害 / インドキシル硫酸 / 腎虚血 / シスプラチン / 酸化ストレス / 薬物排泄 / 薬物トランスポータ / 虚血

Research Abstract

This study was aimed to explore inhibitors of hepatic production of indoxyl sulfate based on uremic toxins which are involved in renal dysfuntion and kidney injury with uremia. By using the screening system for indoxyl sulfate production inhibitors, we found that polyphenolic compounds had potent inhibitory effects on hepatic indoxyl sulfate production. Administration of these polyphenols to rats with acute kidney injury ameliorated the disturbed renal function, suggesting that these approaches could be a useful strategy to develop therapeutic drugs for kidney injuries and/or dieases.

Research Products

• [Journal Article] Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis (2012)
  • Author(s): Kato T, Hamada A, Mori S, Saito H
  • Journal Title: Drug Metab Pharmacokinet Volume: (in press)
  • NAID: 130004463237
• [Journal Article] Effects of Genetic Variants in SLC22A2 Organic Cation Transporter 2 and SLC47A1 Multidrug and Toxin Extrusion 1 Transporter on Cisplatin-induced Adverse Events (2012)
  • Author(s): Iwata K, Aizawa K, Kamitsu S, Jingami S, Fukunaga E, Yoshida M, Yoshimura M, Hamada A, Saito H
  • Journal Title: Clin Exp Nephrol Volume: (in press)
  • NAID: 10031145916
• [Journal Article] Effects of Genetic Variants in SLC22A2 Organic Cation Transporter 2 and SLC47A1 Multidrug and Toxin Extrusion 1 Transporter on Cisplatin-induced Adverse Events (2012)
  • Author(s): Iwata K, et al
  • Journal Title: Clinical & Experimental Nephrology Volume: (掲載確定)
  • Peer Reviewed
• [Journal Article] Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats (2011)
  • Author(s): Kusumoto M, Kamobayashi H, Sato D, Komori M, Yoshimura M, Hamada A, Kohda Y, Tomita K, Saito H
  • Journal Title: Clin Exp Nephrol Volume: 15(6) Pages: 820-830
  • NAID: 10030341588
• [Journal Article] The relationship between treatment time of gemcitabine and development of hematologic toxicity in cancer patients (2011)
  • Author(s): Iwata K, Aizawa K, Sakai S, Jingami S, Fukunaga E, Yoshida M, Hamada A, Saito H
  • Journal Title: Biol Pharm Bull Volume: 34(11) Pages: 1765-1768
  • NAID: 130001252863
• [Journal Article] Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia (2011)
  • Author(s): Yamakawa Y, Hamada A, Shuto T, Yuki M, Uchida T, Kai H, Kawaguchi T, Saito H
  • Journal Title: Clin Pharmacol Ther Volume: 90(1) Pages: 157-163
  • NAID: 120005952465
  • URL: http://hdl.handle.net/2298/23261
• [Journal Article] High-performance liquid chromatographic assay for the determination of nilotinib in human plasma (2011)
  • Author(s): Yuki M, Yamakawa Y, Uchida T, Nambu T, Kawaguchi T, Hamada A, Saito H
  • Journal Title: Biol Pharm Bull Volume: 34(7) Pages: 1126-1128
  • NAID: 130000738108
• [Journal Article] Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia (2011)
  • Author(s): Yamakawa Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T, Saito H
  • Journal Title: Ther Drug Monit Volume: 33(2) Pages: 244-250
  • NAID: 120005952466
• [Journal Article] Association of SLCO1B3 polymorphism with intracellular accumulation of imatinib in leukocytes in patients with chronic myeloid leukemia (2011)
  • Author(s): Nambu T, Hamada A, Nakashima R, Yuki M, Kawaguchi T, Mitsuya H, Saito H
  • Journal Title: Biol Pharm Bull Volume: 34(1) Pages: 114-119
  • NAID: 130000402273
• [Journal Article] Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats (2011)
  • Author(s): Kusumoto M, et al
  • Journal Title: Clinical & Experimental Nephrology Volume: 15 Pages: 820-830
  • Peer Reviewed
• [Journal Article] Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia (2011)
  • Author(s): Yamakawa Y, et al
  • Journal Title: Clinical Pharmacology and Therapeutics Volume: 90 Issue: 1 Pages: 157-163
  • DOI: 10.1038/clpt.2011.102
  • Peer Reviewed
• [Journal Article] Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia. (2011)
  • Author(s): Yamakawa Y, et al.
  • Journal Title: Clinical Pharmacology & Therapeutics Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Association of Genetic Polymorphisms in the Influx Transporter SLCO1B3 and the Efflux Transporter ABCB1 With Imatinib Pharmacokinetics in Patients With Chronic Myeloid Leukemia. (2011)
  • Author(s): Yamakawa Y, et al.
  • Journal Title: Therapeutic Drug Monitoring Volume: 34 Pages: 244-250
  • Peer Reviewed
• [Journal Article] Association of SLCO1B3 polymorphism with intracellular accumulation of imatinib in leukocytes in patients with chronic myeloid leukemia. (2011)
  • Author(s): Nambu T, et al.
  • Journal Title: Biology & Pharmaceutical Bulletin Volume: 34 Pages: 114-119
  • Peer Reviewed
• [Journal Article] Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury : pharmacological and toxicological implications (2010)
  • Author(s): Saito H
  • Journal Title: Pharmacol Ther Volume: 125(1) Pages: 79-91
  • NAID: 120006540420
  • URL: http://hdl.handle.net/2298/13109
• [Journal Article] Contribution of BCR-ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells (2010)
  • Author(s): Nambu T, Araki N, Nakagawa A, Kuniyasu A, Kawaguchi T, Hamada A, Saito H
  • Journal Title: Cancer Sci Volume: 101(1) Pages: 137-142
  • NAID: 10027199844
• [Journal Article] Co-administration of irinotecan decreases the plasma concentration of an active metabolite of amrubicin, amrubicinol in rats (2010)
  • Author(s): Maeda Y, Hamada A, Sanematsu E, Sasaki JI, Yokoo K, Hira A, Saito H
  • Journal Title: Cancer Chemother Pharmacol Volume: 65(5) Pages: 953-959
  • NAID: 120002469644
• [Journal Article] Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury : pharmacological and toxicological implications (2010)
  • Author(s): Saito H
  • Journal Title: Pharmacology and Therapeutics 125 Pages: 79-91
  • NAID: 120006540420
  • Peer Reviewed
• [Journal Article] Contribution of BCR-ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells (2010)
  • Author(s): Nanbu T, et al.
  • Journal Title: Cancer Science 101 Pages: 137-142
  • Peer Reviewed
• [Journal Article] Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats (2009)
  • Author(s): Yokoo K, Murakami R, Matsuzaki T, Yoshitome K, Hamada A, Saito H
  • Journal Title: Clin Exp Nephrol Volume: 13(6) Pages: 578-584
  • NAID: 10027227458
  • URL: http://hdl.handle.net/2298/15589
• [Journal Article] P-Glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines (2009)
  • Author(s): Fujimoto H, Hicuchi M, Watanabe H, Koh Y, Ghosh AK, Mitsuya H, Tanoue N, Hamada A, Saito H
  • Journal Title: Biol Pharm Bull Volume: 32(9) Pages: 1588-1593
  • NAID: 130000117288
• [Journal Article] Acute and chronic metabolic acidosis interferes with aquaporin-2 translocation in the rat kidney collecting ducts (2009)
  • Author(s): Mouri T, Inoue T, Nonoguchi H, Nakayama Y, Miyazaki H, Matsuzaki T, Saito H, Nakanishi T, Kohda Y, Tomita K
  • Journal Title: Hypertens Res Volume: 32(5) Pages: 358-363
  • NAID: 10026122512
• [Journal Article] Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats (2009)
  • Author(s): Yokoo K, et al.
  • Journal Title: Clinical and Experimental Nephrology 13 Pages: 578-584
  • Peer Reviewed
• [Presentation] 抗悪性腫瘍薬の個別動態変動・毒性リスクとトランスポーク介在 (2011)
  • Author(s): 齊藤秀之
  • Organizer: 日本臨床薬理学会第31回年会
  • Place of Presentation: アクトシティ浜松コングレスセンター(静岡県)(招待講演)
  • Year and Date: 2011-12-03
• [Presentation] 有機カチオントランスポータOCT2の遺伝子多型とシスプラチン腎障害との関連 (2011)
  • Author(s): 岩田一史ら
  • Organizer: 第49回日本癌治療学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-27
• [Presentation] シンポジウム20・受容体・トランスポータ研究の最前線:抗悪性腫瘍薬の個別動態変動・毒性リスクとトランスポータ介在 (2011)
  • Author(s): 齋藤秀之
  • Organizer: 第32回日本臨床薬理学会年会
  • Place of Presentation: 浜松
• [Presentation] Genetic variation in the organic cation transporter 2(OCT2) influences the cisplatininduced nephrotoxicity in cancer patients (2011)
  • Author(s): Iwata K, et al.
  • Organizer: 米国腎臓学会第44年会
  • Place of Presentation: フィラデルフィア
• [Presentation] Renoprotective effect of sulfotransferase(SULT) inhibitors on ischemia/reperfusion(IR)-induced acute kidney injury(AKI) rats (2011)
  • Author(s): Komori M, et al.
  • Organizer: 米国腎臓学会第44年会
  • Place of Presentation: フィラデルフィア
• [Presentation] 腎機能低下に伴う経口分子標的治療薬の動態変動と影響因子 (2011)
  • Author(s): 齋藤秀之
  • Organizer: 医療薬学フォーラム2011旭川/クリニカルファーマシーシンポジウム
  • Place of Presentation: 旭川
• [Presentation] 虚血再灌流急性腎障害ラットにおけるSULT阻害薬の尿毒症物質蓄積抑制効果と腎保護作用 (2011)
  • Author(s): 小森めぐみら
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Alleviation of cisplatin-evoked acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats (2011)
  • Author(s): Saito H., et al.
  • Organizer: 第7回国際尿毒症学会
  • Place of Presentation: 名古屋
• [Presentation] 薬剤性腎障害の推定発症機序と早期検出 (2010)
  • Author(s): 齋藤秀之
  • Organizer: 日本臨床薬理学会第31回年会
  • Place of Presentation: 国立京都国際会館(招待講演)
  • Year and Date: 2010-12-01
• [Presentation] Distinct transport characteristics of platinum anticancer drugs, cisplatin and oxaliplatin, in renal tubular epithelial cell line LLC-PK_1 via organic cation transporter and copper transporter (2009)
  • Author(s): Saito H.
  • Organizer: 米国腎臓学会総会2009年会
  • Place of Presentation: サンディエゴコンベンションセンター(米国)
  • Year and Date: 2009-10-30
• [Book] 薬物トランスポータ活用ライブラリー:機能・輸送基質から創薬・臨床応用まで (2009)
  • Author(s): 齋藤秀之, 他
  • Publisher: 洋土社
• [Book] 薬物トランスポーター活用ライブラリー:機能・輸送基質から創薬・臨床応用まで (2009)
  • Author(s): 齋藤秀之, 他
  • Total Pages: 246
  • Publisher: 洋土社
• [Remarks]
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  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/division/results.html
• [Remarks]
  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/division/results.html
• [Remarks]
  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/division/results.html
• [Patent(Industrial Property Rights)] インドキシル硫酸の産生の阻害剤のスクリーニング方法、インドキシル硫酸代謝産生阻害剤、及び腎障害軽減剤 (2010)
  • Inventor(s): 齋藤秀之、濱田哲暢
  • Industrial Property Rights Holder: 国立大学法人熊本大学
  • Industrial Property Number: 2010-234185
  • Filing Date: 2010-10-19
• [Patent(Industrial Property Rights)] インドキシル硫酸の産生の阻害剤のスクリーニング方法、インドキシル硫酸代謝産生阻害剤、及び腎障害軽減剤 (2010)
  • Inventor(s): 齋藤秀之, 濱田哲暢
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Number: 2010-234185
  • Filing Date: 2010-10-19
• [Patent(Industrial Property Rights)] インドキシル硫酸の産生の阻害剤のスクリーニング方法 (2009)
  • Inventor(s): 齋藤秀之, 濱田哲暢
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Number: 2009-240062
  • Filing Date: 2009-10-19