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Studies on the metabolic enzyme involved in the formation of neurotoxic pyridinium metabolite derived from antipsychotic agent

Research Project

Project/Area Number 07672402
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionKOBEGAKUIN UNIVERSITY

Principal Investigator

IGARASHI Kazuo  KOBEGAKUIN UNIVERSITY Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 助教授 (80098467)

Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1996: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1995: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsHaloperidol / Antipsychotic agent / Neurotoxicity / CYP3A / Cytochrome P450 / Peroxygenase / Pyridinium metabolite / Brain transportation / パーキンソン病 / ペルオキシダーゼ / 脳内代謝反応 / P450 / 脳組織内移行 / 薬物代謝酵素 / 肝 / 神経毒性代謝物
Research Abstract

This study was undertaken to examine the metabolic enzyme system involved in the formation neurotoxic pyridinium metabolite derived from antipsychotic agent haloperidol (HP) . The results from metabolic studies have demonstrated that HP is oxidatively converted to the pyridinium metabolite, 4- (4-chlorophenyl) -1- [4- (4-fluorophenyl) -4-oxobutyl] pyridinium species (HPP^+) , which structurally resenbles the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium species (MPP^+) . The conversion is mediated by the CYP3A isoform of cytochrome P450 in liver microsomes of animals and humans. Moreover, the results from incubation with rat brain homogenate have showned that HP is partially oxidized to pyridinium metabolite HPP^+ by peroxygenase system. HPP^+ levels in rat brain increased gradually after intraperitoneal administration of HP.In addition, in vivo microdialysis techniques revealed HPP^+ in rat brain following administration of HP.
These results suggest thst HPP^+ is not formed in the brain but also it may have been formed peripherally and then transported through the blood-brain barrier.

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] K.Igarashi: "Simulatneous determination of haloperidol and its neurotoxic metabolite in plasma and brain of schizophrenic patients" Jpn.J.Forensic Toxicol.13. 31-38 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Studies on the metabolism of haloperidol : The role of CYP3A in the production of the neurotoxic pyridinium metabolite" Life Sci.57. 2439-2446 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving" Neurosci.Lett.214. 183-186 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Analysis of haloperidol and its neurotoxic pyridinium metabolite in biological samples by liquid chromatography/mass spectrometry" Jpn.J.Forensic Toxicol.15. 44-54 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "The possible role of an active metabolite derived from the neuroleptic agent haloperidol in drug-induced parkinsonism" J.Toxicol.Toxin Reviews. 17. 27-38 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 五十嵐一雄: "外因性パーキンソン病発症物質の検索" 日本医用マススペクトル学会サ-キュラー. 37. 1-7 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Simultaneous determination of haloperidol and its neurotoxic metabolite plasma and brain of schizophrenic patients" Jpn. J.Forensic Toxicol.13. 31-38 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Studies on the metabolism of haloperidol : The role of CYP3A in the production of the neurotoxic pyridinium metabolite" Life Sci.57. 2439-2446 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats" Neurosci. Lett.214. 183-186 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Analysis of haloperidol and its neurotoxic pyridinium metabolite biological samples by liquid chromatography/mass spectro-metry" Jpn. J.Forensic Toxicol.15. 44-54 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "The possible role of an active metabolite derived from the neuroleptic agent" J.Toxicol. Toxin Rev.17. 27-38 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "On the exogenous substance induced parkinnsonism (Japanese)" Circlular of JBMS. 37. 1-7 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Igarashi: "Simultaneous determination of haloperidol and its neurotoxic metabolite in plasma and brain of schizophrenic patients" Jpn.J.Forensic Toxicol.13. 31-38 (1995)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Igarashi: "Studies on the metabolism of haloperidol : The role of CYP3A in the production of the neurotoxic pyridinium metabolite" Life Sci.57. 2439-2446 (1995)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Igarashi: "Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats" Neurosci.Lett.214. 183-186 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Igarashi: "Analysis of haloperidol and its neurotoxic pyridinium metabolite in biological samples by liquid chromatography/mass spectrometry" Jpn.J.Forensic Toxicol.15. 44-54 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Igarashi: "The possible role of an active metabolite derived from the neuroleptic agent haloperidol in drug-induced parkinsonism" J.Toxicol.Toxin Reviews. 17. (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Igarashi: "Simultaneous determination of haloperidol and its neurotoxic metabolite in plasma and brain of schizophrenic patients" Jpn.J.Forensic Toxicol.13. 31-38 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Igarashi: "Studies on the metabolism of haloperidol:The role of CYP3A in the production of the neurotoxic pyridinium metabolite" Life Sci.57. 2439-2446 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Igarashi: "Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats" Neuroscience Lett.214. 183-186 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Igarashi: "Analysis of haloperidol and its neurotoxic pyridinium metabolite in biological samples by liquid chromatography/mass spectrometry" Jpn.J.Forensic Toxicol.15. 44-54 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] K. Igarashi: "Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP" Life Sciences. 57 (26). 2439-2446 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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