Bakken Gry V, Molden Espen, Hermann Monica
*Center for Psychopharmacology, Diakonhjemmet Hospital; and †Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
Ther Drug Monit. 2015 Apr;37(2):256-61. doi: 10.1097/FTD.0000000000000135.
To investigate the impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on steady-state serum concentrations of quetiapine and the active metabolite, N-desalkylquetiapine, in psychiatric patients.
Measured serum concentrations of quetiapine and N-desalkylquetiapine from patients with biobanked DNA samples were included retrospectively from a routine therapeutic drug monitoring database. The impact of CYP2D6, CYP3A5, and ABCB1 (345C>T) genotypes on dose-adjusted serum concentrations (C/D ratios) of quetiapine and N-desalkylquetiapine was investigated by multivariate mixed model analysis.
In total, 289 patients with 633 serum measurements were included. In the multivariate analysis, mean C/D ratio of N-desalkylquetiapine was estimated to be 33% and 22% higher in inherent CYP2D6 poor metabolizers (P = 0.03) and heterozygous extensive metabolizers (P < 0.001), respectively, compared with inherent extensive metabolizers. The ABCB1 3435C>T polymorphism and CYP3A5 genotype had no significant influence on either of the substances in the present material.
Genetic variability in CYP2D6 contributes to the interindividual variability in steady-state serum concentrations of N-desalkylquetiapine. Although the metabolite exhibits relevant pharmacological activity, the quantitative effect of CYP2D6 genotype on serum concentration of N-desalkylquetiapine is probably of limited clinical relevance for quetiapine treatment.
研究CYP2D6、CYP3A5和ABCB1基因变异对精神科患者喹硫平及其活性代谢物N-去烷基喹硫平稳态血清浓度的影响。
从常规治疗药物监测数据库中回顾性纳入有生物样本库DNA样本患者的喹硫平和N-去烷基喹硫平实测血清浓度。通过多变量混合模型分析研究CYP2D6、CYP3A5和ABCB1（345C>T）基因型对喹硫平和N-去烷基喹硫平剂量调整血清浓度（C/D比值）的影响。
共纳入289例患者，进行了633次血清测量。多变量分析中，与固有广泛代谢者相比，固有CYP2D6慢代谢者（P = 0.03）和杂合广泛代谢者（P < 0.001）的N-去烷基喹硫平平均C/D比值分别估计高33%和22%。ABCB1 3435C>T多态性和CYP3A5基因型对本研究中的任何一种物质均无显著影响。
CYP2D6基因变异导致N-去烷基喹硫平稳态血清浓度的个体间差异。尽管该代谢物具有相关药理活性，但CYP2D6基因型对N-去烷基喹硫平血清浓度的定量影响在喹硫平治疗中可能临床相关性有限。
