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

(1)研究了基因型CYP2D6对41名日本精神病人群去甲替林（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。经剂量和体重校正的NT浓度在无突变等位基因组与有突变等位基因组之间存在显著差异（无突变等位基因vs有突变等位基因组= 70.3±25.4 (mean±s.d) vs 98.4±36.6 ng/ml/mg/kg B.W., p<0.05），在无突变等位基因组与有突变等位基因组之间存在显著差异（无突变等位基因vs有突变等位基因组= 70.3±25.4 vs 147±31.1 ng/ml/mg/kg B.W., p<0.0001）。无等位基因突变组和有两个等位基因突变组的NT/EHNT（代表NT羟基化比率）也有显著差异（无突变等位基因vs两个突变等位基因= 0.82±0.30 vs 2.71±0.84,p<0.0001）。(2)我们研究了18例服用盐酸地西帕明的患者CYP2D6基因型对地西帕明羟基化的影响。2个等位基因突变组地西帕明血药浓度/地西帕明日剂量/体重比1个等位基因突变组高（2个等位基因突变vs 1个等位基因突变= 530.4±215.2 vs 118.1±63.9 ng/ml/mg/kg, p<0.001； 2个等位基因突变vs 1个等位基因突变= 530.4±215.2 vs 176.2±62.3 ng/ml/mg/kg, p<0.001）。2个等位基因突变组地西帕明/2-羟基地西帕明比值显著高于1个或2个等位基因突变组（2个等位基因突变vs 1个等位基因突变= 4.39±0.36 vs 2.00±0.64,p<0.001； 2个等位基因突变vs 1个等位基因突变= 4.39±0.36 vs 2.02±0.59,p<0.01）。

(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).