*Center for Psychopharmacology, Diakonhjemmet Hospital; and †Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
Ther Drug Monit. 2014 Feb;36(1):80-5. doi: 10.1097/FTD.0000000000000018.
Cytochrome P450 2D6 intermediate metabolizer phenotype (CYP2D6 IM) comprises various genotype subgroups. The aim of this study was to evaluate serum concentrations of the CYP2D6 substrates risperidone and aripiprazole in psychiatric patients with various CYP2D6 genotypes encoding IM phenotype.
The study was based on therapeutic drug monitoring data from CYP2D6-genotyped patients (mainly of white origin) treated with orally administered risperidone (n = 190) or aripiprazole (n = 266). Patients were divided into 3 genotype subgroups encoding IM phenotype: (1) heterozygous carriers of fully functional and nonfunctional variant alleles (*1/def), (2) homozygous carriers of reduced-function variant alleles (red/red), and (3) heterozygous carriers of reduced-function and nonfunctional variant alleles (def/red). Dose-adjusted serum concentrations of risperidone and aripiprazole were compared between the genotype subgroups using *1/def, the most frequent CYP2D6 genotype among these subgroups, as the reference group.
Median serum concentrations were 4.5- and 1.6-fold higher in the def/red genotype than the *1/def genotype for risperidone and aripiprazole, respectively (P < 0.01 for both). Correspondingly, the serum concentrations were 3.4- and 1.8-fold higher in the red/red subgroup compared with the reference group (P < 0.05 for both).
In conclusion, this study revealed substantial variability in serum concentrations of risperidone and aripiprazole between CYP2D6 genotypes associated with IM phenotype. A considerable phenotypical difference was observed between patients carrying 1 and 2 variant alleles.
细胞色素 P450 2D6 中间代谢表型（CYP2D6 IM）包含各种基因型亚组。本研究旨在评估具有各种 CYP2D6 基因型（编码 IM 表型）的精神科患者中 CYP2D6 底物利培酮和阿立哌唑的血清浓度。
该研究基于接受口服利培酮（n = 190）或阿立哌唑（n = 266）治疗的 CYP2D6 基因分型患者（主要为白种人）的治疗药物监测数据。患者被分为编码 IM 表型的 3 种基因型亚组：（1）完全功能性和非功能性变异等位基因（*1/def）的杂合子携带者，（2）减少功能变异等位基因（red/red）的纯合子携带者，和（3）减少功能和非功能性变异等位基因（def/red）的杂合子携带者。使用这些亚组中最常见的 CYP2D6 基因型（*1/def）作为参考组，比较基因型亚组之间利培酮和阿立哌唑的剂量调整血清浓度。
利培酮和阿立哌唑在 def/red 基因型中的血清浓度中位数分别比*1/def 基因型高 4.5 倍和 1.6 倍（两者均 P < 0.01）。相应地，red/red 亚组的血清浓度比参考组高 3.4 倍和 1.8 倍（两者均 P < 0.05）。
总之，本研究揭示了与 IM 表型相关的 CYP2D6 基因型之间利培酮和阿立哌唑血清浓度的显著变异性。携带 1 个和 2 个变异等位基因的患者之间存在明显的表型差异。
