1999 Fiscal Year Final Research Report Summary
Clnical pharmacological and molecular genetic study on the development of rational antipsychotic therapy
| Project/Area Number |
09670985
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Psychiatric science
|
|---|
| Research Institution | Shiga 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
|
| Keywords | Antipsychotics / 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
|
