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1999 Fiscal Year Final Research Report Summary

Clnical pharmacological and molecular genetic study on the development of rational antipsychotic therapy

Research Project

Project/Area Number 09670985
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionShiga University of Medical Science

Principal Investigator

SHINODA Kazutaka  Shiga University of Medical Science, Department of Psychiatry, Lecturer, 医学部, 講師 (30196555)

Co-Investigator(Kenkyū-buntansha) SOMEYA Toshiyuki  Niigata University School of Medicine, Department of Psychiatry, Professor, 医学部, 教授 (50187902)
Project Period (FY) 1997 – 1999
KeywordsAntipsychotics / Metabolism / Interindividual difference / Cytochrome P450 / Genetic analysis
Research Abstract

Plasma levels of timiperone and reduced timiperone were determined in 10 schizophrenic patients who were treated with timiperone. Given 0.3 mg/kg of timiperone, a plasma level of timiperone was predicted as 60% of that of haloperidol. The activity if timiperone reductase in RBC was determined as approximately 70% of haloperidol reductase in RBC.
In vitro studies using human liver cytosol was undertaken in order to compare the mechanism if reduction of timiperone with that of haloperidol. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of reduced timiperone was 1.3-2.4 fold higher than for haloperidol, indicating that metabolic clearance of timiperone by carbonyl reductase may be similar to or slightly higher than for haloperidol.
We analyzed data from 231 schizophrenic inpatients and the subjects who received carbamazepine concomitantly had 37 % lower mean haloperidol concentration/dose ratio than the subject without carbamazepine. The subjects treated with concomitant phe … More nobarbital showed 22% lower mean haloperidol concentration/dose ratio than the subjects without phenobarbital.
The impact of smoking on plasma haloperidol concentrations was investigated in sixty-six schizophrenic patients treated with haloperidol. Smokers has significantly lower haloperidol concentrations/daily dose of haloperidol/kg body weight than non-smokers.
We investigated the relationship between plasma haloperidol levels and the number of CYP2D6 mutated alleles in seventy-one Japanese schizophrenic inpatients. No significant difference in the plasma haloperidol levels were observed between the subjects with no, one and two ィイD1*ィエD110 alleles.
We also investigated the impact of the genotype of CYP2D6 on the hydroxylation of desipramine in eighteen patients who were administered desipramine. Significantly higher plasma concentration of desipramine/daily dose of desipramine/body weight and the ratio of despramine/2-hydroxy-desipramine were observed in the subjects with two mutated alleles than in the subjects with no mutated alleles or one mutated allele. Less

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] K. Shimoda: "Carbonyl reduction of timiperone in human liver cytosol"Pharmacology and Toxicology. 83. 164-168 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Shimoda: "Plasma concentrations of timiperone and its reduced metabolite in patients on timiperone"Psychiatry and Clinical Neuroscience. 52. 535-540 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] G. Hirokane: "Interindividual variation of plasma haloperidol concentrations and the impact of concomitant me dications : the analysis of therapeutic drug monitoring data"Therapeutic Drug Monitoring. 21. 82-86 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Shimoda: "Lower plasma levels of haloperidol in smoking than in non-smoking schizophrenic patients"Therapeutic Drug Monitoring. 21. 293-296 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Someya: "The effect of cytochrome P450 2D6 genetypes on haloperidol metabolism in Japanese psychiatric patients : Preliminary report"Psychiatry and Clinical neuroscience. 53. 593-597 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Shimoda: "CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Oriental patients"Therapeutic Drug Monitoring. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Shimoda: "Significance of monitoring plasma levels of amitriptyline, its hydroxylated and desmethylated metabolites in prediction of clinical outcome of depressive state"Psychiatry and Clinical Neuroscience. 51(1). 35-41 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K. Shimoda: "Carbonyl reduction of timiperone in human liver cytosol"Pharmacology & Toxicology. 83. 164-168 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K. Shimoda: "Plasma concentration of timiperone and its reduced metabolite in the patients on timiperone"Psychiatry and Clinical Neuroscience. 52. 535-540 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] G. Hirokane: "Interindividual variation of plasma haroperidol concentrations and the impact of concomitant medications : the analysis of therapeutic drug monitoring data"Therapeutic Drug Monitoring. 21. 82-86 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K. Shimoda: "Lower plasma levels of haloperidol in smoking than in non-smoking schizophrenic patients"Therapeutic Drug Monitoring. 21. 293-296 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K. Shimoda: "Pronounced differences in the kinetics of clomipramine between Japanese and Swedish patients"Journal of Clinical Psychopharmacology. 19. 393-400 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T. Someya: "The effect of cytochrome P450 2D6 genotypes on haloperiodal metabolism in Japanese psychiatric patients : A preliminary report"Psychiatry and Clinical Neuroscience. 53. 593-597 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T. Someya: "Interindividual variation in bromperidol metabolism and relationship with therapeutic effects"Journal of Clinical Psychopharmacology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S. Morita: "Steady-state plasma levels of nortriptyline and its hydroxylated metabolites : The impact of CYP2D6 genotype on the hydroxylation of nortriptyline"Journal of Clinical Psychopharmacology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K. Shimoda: "Metabolism of desipramine in Japanese psychiatric patients : The impact of CYP2D6 genotype on the hydroxylation of desipramine"Pharmacology & Toxicology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K. Shimoda: "CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentration in Oriental patients"Therapeutic Drug Monitoring. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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