Hendset Magnhild, Hermann Monica, Lunde Hilde, Refsum Helge, Molden Espen
Department of Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway.
Eur J Clin Pharmacol. 2007 Dec;63(12):1147-51. doi: 10.1007/s00228-007-0373-6. Epub 2007 Sep 9.
Aripiprazole is an atypical antipsychotic drug which is metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). The aim of the present study was to investigate the impact of the CYP2D6 genotype on serum concentrations of aripiprazole (ARI) and to determine the sum of ARI and the active metabolite dehydroaripiprazole (DARI) in psychiatric patients.
Data on steady-state serum concentrations and the CYP2D6 genotypes of patients treated with ARI were extracted from a routine therapeutic drug monitoring database. The 62 patients included in the analysis were stratified into the following subgroups according to CYP2D6 genotype: *1/*1 (homozygous extensive metabolizers, EMs; n = 37), *1/*3-6 (heterozygous extensive metabolizers, HEMs; n = 17) and *3-6/*3-6 (poor metabolizers, PMs; n = 8). Dose-adjusted serum concentrations (C/D ratios) of ARI and ARI + DARI were compared between the subgroups.
The median serum concentration of ARI was 1.7-fold higher in PMs than in EMs (45.5 vs. 26.3 nM/mg, p < 0.01). The observed serum concentration of the active sum of ARI + DARI was 1.5-fold higher in PMs than in EMs (53.9 vs. 37.0 nM/mg, p < 0.05). Numerical differences in serum concentrations between HEMs and EMs were less pronounced, but statistically significant for both ARI (p < 0.05) and ARI + DARI (p < 0.05).
The present study demonstrates that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients were significantly affected by CYP2D6 genotype. The observed differences in median C/D ratios indicate that PMs typically need 30-40% lower doses to achieve a similar steady-state serum concentration as EMs.
阿立哌唑是一种非典型抗精神病药物，由多态性酶细胞色素P450 2D6（CYP2D6）代谢。本研究的目的是调查CYP2D6基因型对阿立哌唑（ARI）血清浓度的影响，并确定精神科患者中ARI与活性代谢物脱氢阿立哌唑（DARI）的总和。
从常规治疗药物监测数据库中提取接受ARI治疗患者的稳态血清浓度和CYP2D6基因型数据。纳入分析的62例患者根据CYP2D6基因型分为以下亚组：*1/*1（纯合子广泛代谢者，EMs；n = 37），*1/3 - 6（杂合子广泛代谢者，HEMs；n = 17）和3 - 6/*3 - 6（慢代谢者，PMs；n = 8）。比较各亚组之间ARI和ARI + DARI的剂量调整血清浓度（C/D比值）。
PMs中ARI的血清浓度中位数比EMs高1.7倍（45.5对26.3 nM/mg，p < 0.01）。观察到的ARI + DARI活性总和的血清浓度在PMs中比EMs高1.5倍（53.9对37.0 nM/mg，p < 0.05）。HEMs和EMs之间血清浓度的数值差异不太明显，但对于ARI（p < 0.05）和ARI + DARI（p < 0.05）均具有统计学意义。
本研究表明，精神科患者中ARI以及ARI + DARI的活性总和的血清浓度均受到CYP2D6基因型的显著影响。观察到的中位数C/D比值差异表明，PMs通常需要比EMs低30 - 40%的剂量才能达到相似的稳态血清浓度。
