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Mechanisms responsible for interindividual variability of bioavailability of therapeutic compounds in patients with acute renal failure and related homeostasis perturbation

Research Project

Project/Area Number 18590141
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionOkayama University

Principal Investigator

AIBA Tetsuya  Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Ph.D.Associate Profrssor (00231754)

Co-Investigator(Kenkyū-buntansha) KUROSAKI Yuji  Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Ph.D.S, Professor (90161786)
KAWASAKI Hiromu  Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Ph.D.Professor (60125151)
KOMORI Yukiko  Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, M.Sc.Research Instructor (80379734)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,830,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsRenal failure / Pharmacokinetics / Cephalexin / Tolhutamide / unidine / NKCCl / TRPVl / Pharmacodynamics / 消化管神経叢 / 尿毒症物質 / アベイラビリティ / 腹膜透析 / タンパク結合 / 分布容積
Research Abstract

Mechanisms responsible for blood concentration of therapeutic compounds being considerably altered in acute renal failure were investigated. It was shown that protein unbound fraction of a representative compound quinidine is decreased in acute renal failure, whereas those of acid compounds, such as tolbutamide, has been known to be increased. The decreased unbound fraction of quinidine seems to be related to the fact that the hepatic production of alpha-1 acid glycoprotein (AGP) increases in acute renal failure, resulting in an increase in the plasma AGP concentration. In addition, we revealed that lithium disposition to cerebrospinal fluid (CSF) decreases when the kidney function is impaired, and that the choroid plexial expression of NKCC1 increases in acute renal failure. Therefore, it is plausible that the decreased lithium disposition to CSF is caused by an increased lithium efflux from CSF due to an increased NKCC1 expression in the choroid plexus. We also found that the transporter-mediated intestinal absorption of cephalexin is suppressed by stimulating a cation channel TRPV1 expressed on afferent neurons innervating gastro-intestinal tract. As afferent neurons seem to play an important role in regulating intestinal drug absorption and its alternation in acute renal failure, future study should be conducted to clarify this.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (38 results)

All 2008 2007 2006 Other

All Journal Article (16 results) (of which Peer Reviewed: 9 results) Presentation (22 results)

  • [Journal Article] Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children2008

    • Author(s)
      Satoshi Ueshima, et. al.
    • Journal Title

      Journal of Clinical Pharmacy and Therapeutics 31

      Pages: 33-38

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Decreased lithium disposition to cerebrospinal fluid in rats with glycerol-induced acute renal failure2008

    • Author(s)
      Rie Sakae, et. al.
    • Journal Title

      Pharmaceutical Research (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children2008

    • Author(s)
      Satoshi, Ueshima, et. al.
    • Journal Title

      Journal of Clinical Pharmacy and Therapeutics 31(1)

      Pages: 33-38

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Effects of capsaicin on intestinal cephalexin absorption in rats2007

    • Author(s)
      Yukiko Komori, et. al.
    • Journal Title

      Biological and Pharmaceutical Bulletin 30

      Pages: 547-551

    • NAID

      110006239201

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Alteration of therapeutic efficacy of lipid microspheres incorporating prostaglandin E1 by mixing with aqueous solution2007

    • Author(s)
      Yukiko Komori, et. al.
    • Journal Title

      Journal of Pharmaceutical Sciences 96

      Pages: 935-943

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Capsaicin-induced increase of intestinal cefazolin absorption in rats2007

    • Author(s)
      Yukiko Komori, et. al.
    • Journal Title

      Drug Metabolism and Pharmacokinetics 22

      Pages: 445-449

    • NAID

      10020163654

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats2007

    • Author(s)
      Yukiko Komori, et. al.
    • Journal Title

      International Journal of Pharmaceutics 343

      Pages: 190-195

    • NAID

      120002307079

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Effects of capsaicin on intestinal cephalexin absorption in rats2007

    • Author(s)
      Yukiko, Komori, et. al.
    • Journal Title

      Biological and Pharmaceutical Bulletin 30(3)

      Pages: 547-551

    • NAID

      110006239201

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Alteration of therapeutic efficacy of lipid microspheres incorporating prostaglandin El by mixing with aqueous solution2007

    • Author(s)
      Yukiko, Komori, et. al.
    • Journal Title

      Journal of Pharmaceutical Sciences 96(4)

      Pages: 935-943

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Capsaicin-induced increase of intestinal cefazolin absorption in rats2007

    • Author(s)
      Yukiko, Komori, et. al.
    • Journal Title

      Drug Metabolism and Pharmacokinetics 22(6)

      Pages: 445-449

    • NAID

      10020163654

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats2007

    • Author(s)
      Yuji, Kurosaki, et. al.
    • Journal Title

      International Journal &Pharmaceutics 343(1-2)

      Pages: 190-195

    • NAID

      120002307079

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Alteration of therapeutic efficacy of lipid microspheres incorporating prostaglandin El by mixing with aqueous solution2007

    • Author(s)
      Yukiko Komori, et. al.
    • Journal Title

      Journal of Pharmaceutical Sciences 96

      Pages: 935-943

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats2007

    • Author(s)
      Yuji Kurosaki, et. al.
    • Journal Title

      International Journal of Pharmaceutics 343

      Pages: 190-195

    • NAID

      120002307079

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peritoneal dialysis alters tolbutamide pharmacokinetics in rats with experimental acute renal failure2006

    • Author(s)
      Tetsuya Aiba, et. al.
    • Journal Title

      Drug Metabolism and Pharmacokinetics 21

      Pages: 291-296

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Peritoneal dialysis alters tolbutamide pharmacokinetics in rats with experimental acute renal failure2006

    • Author(s)
      Tetsuya, Aiba, et. al.
    • Journal Title

      Drug Metabolism and Pharmacokinetics 21(4)

      Pages: 291-296

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Decreased lithium disposition to cerebrospinal fluid in rats with glycerol-induced acute renal failure

    • Author(s)
      Rie, Sakae, et. al.
    • Journal Title

      Pharmaceutical Research (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 乳幼児における血中遊離形バルプロ酸の遡及的解析2007

    • Author(s)
      合葉哲也, ら
    • Organizer
      第28回日本臨床薬理学会年会
    • Place of Presentation
      栃木県宇都宮市
    • Year and Date
      2007-11-29
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Retrospective analysis of unbound valproate fraction in Japanese epileptic children2007

    • Author(s)
      Tetsuya, Aiba, et. al.
    • Organizer
      The 28th Annual Meeting of the Japanese Society of Clinical Pharmacology and Therapeutics
    • Place of Presentation
      in Utsunomiya City, Tochigi
    • Year and Date
      2007-11-29
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 乳幼児の発育に伴う血中遊離形バルプロ酸濃度の変動評価2007

    • Author(s)
      石川七瀬, ら
    • Organizer
      第46回日本薬学会・日本病院薬剤師会中国四国支部学術大会
    • Place of Presentation
      高知県高知市
    • Year and Date
      2007-11-11
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] 脈絡叢の電解質輸送機構に及ぼす腎不全の影響2007

    • Author(s)
      石川温子, ら
    • Organizer
      第46回日本薬学会・日本病院薬剤師会中国四国支部学術大会
    • Place of Presentation
      高知県高知市
    • Year and Date
      2007-11-11
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Interindividual variability of unbound fraction of valproic acid in epileptic neonates and infants2007

    • Author(s)
      Nanase, Ishikawa, et. al.
    • Organizer
      The 46th Annual Regional Meeting of the Pharmaceutical Society of Japan in Chugoku-Shikoku
    • Place of Presentation
      in Kochi City
    • Year and Date
      2007-11-11
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of acute renal failure on choroid plexial electrolyte transport in rats2007

    • Author(s)
      Atsuko, Ishikawa, et. al.
    • Organizer
      The 46th Annual Regional Meeting of the Pharmaceutical Society of Japan in Chugoku-Shikoku
    • Place of Presentation
      in Kochi City
    • Year and Date
      2007-11-11
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] てんかん患児における遊離形バルプロ酸濃度に及ぼす併用薬の影響2007

    • Author(s)
      上島智, ら
    • Organizer
      第24回日本TDM学会・学術大会
    • Place of Presentation
      石川県金沢市
    • Year and Date
      2007-07-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Unbound fraction of valproic acid in pediatric patients with epilepsy receiving combination therapy2007

    • Author(s)
      Satoshi, Ueshima, et. al.
    • Organizer
      The 24th Annual Meeting of Japanese Society of Therapeutic Drug Monitoring
    • Place of Presentation
      in Kanazawa City, Ishikawa
    • Year and Date
      2007-07-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 薬物の腸管吸収におけるバニロイド受容体による生理的制御2007

    • Author(s)
      小森有希子, ら
    • Organizer
      日本薬剤学会第22年会
    • Place of Presentation
      埼玉県大宮市
    • Year and Date
      2007-05-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Physiological regulation of intestinal drug absorption via vanilloid receptor2007

    • Author(s)
      Yukiko, Komori, et. al.
    • Organizer
      The 22nd Annual Meeting of the Academy of Pharmaceutical Science and Technology
    • Place of Presentation
      in Ohmiya City, Saitama
    • Year and Date
      2007-05-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 抗躁薬リチウムの脳脊髄液移行性におよぼす腎不全の影響2007

    • Author(s)
      二宗朋子, ら
    • Organizer
      日本薬学会第127年会
    • Place of Presentation
      富山県富山市
    • Year and Date
      2007-03-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of acute renal failure on lithium CSF disposition in rats2007

    • Author(s)
      Tomoko, Niso, et. al.
    • Organizer
      The 127th Annual Meeting of the Pharmaceutical Society of Japan
    • Place of Presentation
      in Toyama City
    • Year and Date
      2007-03-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 腹膜透析ラットにおけるトルブタミドの体内動態に及ぼすサルファ剤の影響2006

    • Author(s)
      槙田崇志, ら
    • Organizer
      第21回日本薬物動態学会年会
    • Place of Presentation
      東京都江戸川区
    • Year and Date
      2006-11-30
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of sulfonamides on tolbutamide pharmacokinetics in rats receiving peritoneal dialysis2006

    • Author(s)
      Takashi, Makita, et. al.
    • Organizer
      The 21st Annual Meeting of the Japanese Society for the Study of Xenobiotics
    • Place of Presentation
      in Edogawa Ward, Tokyo
    • Year and Date
      2006-11-30
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] トルブタミドの腹膜透析性に及ぼすサルファ剤の影響2006

    • Author(s)
      出羽祐基, ら
    • Organizer
      第45回日本薬学会・日本病院薬剤師会中国四国支部学術大会
    • Place of Presentation
      広島県広島市
    • Year and Date
      2006-10-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] マイクロダイアリシス法による抗躁薬リチウムの脳移行動態とその変動性の解析2006

    • Author(s)
      坂江利恵, ら
    • Organizer
      第45回日本薬学会・日本病院薬剤師会中国四国支部学術大会
    • Place of Presentation
      広島県広島市
    • Year and Date
      2006-10-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] バニロイド受容体刺激が消化管からの薬物吸収に及ぼす影響(第2報)2006

    • Author(s)
      中江千絵, ら
    • Organizer
      第45回日本薬学会・日本病院薬剤師会中国四国支部学術大会
    • Place of Presentation
      広島県広島市
    • Year and Date
      2006-10-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of sulfonamides on peritoneal dialysis of tolbutamide in rats2006

    • Author(s)
      Yuki, Izuwa, et. al.
    • Organizer
      The 45th Annual Regional Meeting of the Pharmaceutical Society of Japan in Chugoku-Shikoku
    • Place of Presentation
      in Hiroshima City
    • Year and Date
      2006-10-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Microdialysis study of lithium pharmacokinetic and CSF disposition in rats2006

    • Author(s)
      Rie, Sakae, et. al.
    • Organizer
      The 45th Annual Regional Meeting of the Pharmaceutical Society of Japan in Chugoku-Shikoku
    • Place of Presentation
      in Hiroshima City
    • Year and Date
      2006-10-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Effects of stimulation via vanilloid receptor on intestinal drug absorption profile in rats2006

    • Author(s)
      Chie, Nakai, et. al.
    • Organizer
      The 45th Annual Regional Meeting of the Pharmaceutical Society of Japan in Chugoku-Shikoku
    • Place of Presentation
      in Hiroshima City
    • Year and Date
      2006-10-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] バルプロ酸TDMデータの遡及的解析2006

    • Author(s)
      槙田崇志, ら
    • Organizer
      第16回日本医療薬学会年会
    • Place of Presentation
      石川県金沢市
    • Year and Date
      2006-10-01
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Retrospective analysis of valproic acid pharmacokinetics in patients based on observations via TDM activities2006

    • Author(s)
      Takashi, Makita, et. al.
    • Organizer
      The 16th Annual Meeting of Japanese Society of Pharmaceutical health care and Sciences
    • Place of Presentation
      in Kanazawa City, Ishikawa
    • Year and Date
      2006-10-01
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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