Molecular pharmacogenetic study on the marker for drug response in refractory depressive patients

难治性抑郁症患者药物反应标志物的分子药理学研究

• 批准号: 10670897
• 负责人: SOMEYA Toshiyuki
• 金额: $ 2.05万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670897/
• 关键词: Refractory Depression; Tricyclic Antidepressants; drug metabolism; CYP2D6

(1) We investigated the impact of genotype of CYP2D6 on steady-state concentrations of nortriptyline (NT) and its metabolites, trans-10-hydroxy-nortriptyline (EHNT) and cis-10-hydroxy-nortriptyline (ZHNT) in 41 Japanese psychiatric population. Significant differences in NT concentrations corrected for dose and weight were observed between the subjects with no mutated allele and the subjects with one mutated allele (no mutated allele vs one mutated allele = 70.3 ± 25.4 (mean ± s.d.) vs 98.4 ± 36.6 ng/ml/mg/kg B.W., p<0.05), and also between the subjects with no mutated allele and two mutated alleles (no mutated allele vs two mutated alleles = 70.3 ± 25.4 vs 147 ± 31.1 ng/ml/mg/kg B.W., p<0.0001). Also significant difference in NT/EHNT, which is representative of the hydroxylation ratio of NT, was observed between the subjects with no mutated allele and the subjects with two mutated alleles (no mutated allele vs two mutated alleles = 0.82 ± 0.30 vs 2.71 ± 0.84, p<0.0001).(2) We investigated the impact of the genotype of CYP2D6 on the hydroxylation of desipramine in eighteen patients who were administered desipramine hydrochloride per os. Significantly higher plasma concentration of desipramine/daily dose of desipramine/body weight was observed in the subjects with two mutated alleles than in the subjects with either no mutated alleles or one mutated allele (two mutated alleles vs no mutated alleles = 530.4 ± 215.2 vs 118.1 ± 63.9 ng/ml/mg/kg, p<0.001 ; two mutated alleles vs one mutated allele = 530.4 ± 215.2 vs 176.2 ± 62.3 ng/ml/mg/kg, p<0.001). Significantly higher ratio of desipramine/2-hydroxy-desipramine was observed in the subjects with two mutated alleles compared to subjects with no mutated alleles or the subjects with one mutated allele (two mutated alleles versus one mutated allele = 4.39± 0.36 vs 2.00 ± 0.64, p<0.001 ; two mutated alleles vs no mutated alleles = 4.39 ± 0.36 vs 2.02 ± 0.59, p<0.01).

(1)我们研究了41名日本精神病患者CYP 2D 6基因型对去甲替林（NT）及其代谢产物反式-10-羟基去甲替林（EHNT）和顺式-10-羟基去甲替林（ZHNT）稳态浓度的影响。在没有突变等位基因的受试者和具有一个突变等位基因的受试者之间观察到针对剂量和体重校正的NT浓度的显著差异（没有突变等位基因对一个突变等位基因= 70.3 ± 25.4（平均值± s.d.）vs 98.4 ± 36.6 ng/ml/mg/kg B.W.，p<0.05），以及在没有突变等位基因和两个突变等位基因的受试者之间（没有突变等位基因对两个突变等位基因= 70.3 ± 25.4对147 ± 31.1 ng/ml/mg/kg B.W.，p<0.0001）。在没有突变的等位基因的受试者和具有两个突变的等位基因的受试者之间也观察到代表NT的羟基化比率的NT/EHNT的显著差异（没有突变的等位基因对两个突变的等位基因= 0.82 ± 0.30对2.71 ± 0.84，p<0.0001）。(2)我们研究了CYP 2D 6基因型对18例口服盐酸地昔帕明的患者的地昔帕明羟化的影响。观察到两个突变等位基因的受试者的地昔帕明血浆浓度/地昔帕明日剂量/体重显著高于无突变等位基因或一个突变等位基因的受试者（两个突变的等位基因对无突变的等位基因= 530.4 ± 215.2对118.1 ± 63.9 ng/ml/mg/kg，p<0.001 ;两个突变的等位基因对一个突变的等位基因= 530.4 ± 215.2对176.2 ± 62.3 ng/ml/mg/kg，p<0.001）。与无突变等位基因或有一个突变等位基因的受试者相比，在有两个突变等位基因的受试者中观察到显著更高的地昔帕明/2-羟基-地昔帕明比率（2个突变等位基因对1个突变等位基因= 4.39± 0.36对2.00 ± 0.64，p<0.001 ;两个突变等位基因与无突变等位基因的比值分别为4.39 ± 0.36和2.02 ± 0.59，P<0.01。

项目成果

Someya,T.et al.: "Interindividual variation in bromperidol metabolism and its relationship with therapeutic effects"Journal of Clinical Psychopharmacology. (in press).

Someya,T.et al.：“溴哌啶醇代谢的个体差异及其与治疗效果的关系”临床精神药理学杂志。

Someya, T., Muratake, T., Hirokane, G., Shibasaki, M., Shimoda, K. and Takahashi, S.: "Interindividual variation in bromperidol metabolism and its relationship with therapeutic effects."J Clin Psychopharmacol. (in press).

Someya, T.、Muratake, T.、Hirokane, G.、Shibasaki, M.、Shimoda, K. 和 Takahashi, S.：“溴哌啶醇代谢的个体差异及其与治疗效果的关系。”J Clin Psychopharmacol。

Morita ,S.et al.: "Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese: The impact of CYP2D6 genotype on the hydroxylation of nortriptyline"Journal of Clinial Psychopharmacology. in press.

Morita,S.等人：“去甲替林及其羟基化代谢物的稳态血浆水平（日语：CYP2D6 基因型对去甲替林羟基化的影响）”临床精神药理学杂志。

Shimoda,K.et al.: "Metabolism of desipramine in Japanese psychiatric patients: The impact of CYP2D6 genotype on the hydroxylation of desipramine"Pharmacology and Toxicology. (in press).

Shimoda,K.等人：“日本精神病患者中地昔帕明的代谢：CYP2D6 基因型对地昔帕明羟基化的影响”药理学和毒理学。

Someya, T. et al: "Interindividual variation in bromperiodol metabolism and its relationship with therapeutic effects"Journal of Clinical Psychopharmacology. (in press).

Someya, T. 等人：“溴周期醇代谢的个体差异及其与治疗效果的关系”临床精神药理学杂志。