The role of CYP2D6 and ABCB1 pharmacogenetics in drug-na⟨ve patients with first-episode schizophrenia treated with risperidone
The role of CYP2D6 and ABCB1 pharmacogenetics in drug-na⟨ve patients with first-episode schizophrenia treated with risperidone
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DOI：
10.1007/s00228-010-0850-1
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发表时间：
2010-11-01
影响因子：
2.9
通讯作者：
Peles, Alma Mihaljevic
中科院分区：
文献类型：
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作者：
Jovanovic, Nikolina;Bozina, Nada;Peles, Alma Mihaljevic
旨在评估细胞色素 450 2D6 (CYP2D6) 和 ABCB1 变体对 83 名首次经历精神病发作的初治患者血浆利培酮浓度和治疗反应的作用。所有患者均接受利培酮治疗 8 周。 CYP2D6 基因分型通过等位基因特异性 PCR 限制性片段长度多态性分析（针对等位基因 *3、*4、*6）和长距离 PCR（针对重复和等位基因 *5）进行，而实时 PCR 分析则用于 ABCB1 G2677T/A 和 C3435T 变体。采用高效液相色谱法测定利培酮和9-OH利培酮的血浆浓度。CYP2D6野生型(wt)/wt、wt/突变(mut)和mut/mut基因型的患者人数分别为43、32和8。携带 ABCB1 2677G/G、G/T 和 T/T 变异的患者人数分别为 29 例、42 例和 12 例； 3435CC、C/T 和 T/T 变体的数量分别为 25、37 和 21。 CYP2D6 基因型对利培酮、其 9-OH 代谢物和活性部分的稳态剂量校正血浆水平 (C/D) 有强烈影响，而 ABCB1 2677 T/T 和 3435 T/T 基因型对活性部分 C/D 也有类似的强烈影响。 CYP2D6 弱代谢者的利培酮 C/D 和活性部分 C/D 显着较高，而 9-OH 利培酮 C/D 较低。 ABCB1 3435 T 等位基因和 ABCB1 2667 T-3435 T 单倍型携带者在无锥体外系综合征的受试者中更为常见。患者的阳性症状和一般症状有显着改善，但阴性症状没有明显改善。这些变化与遗传和药物浓度数据的变化无关。我们的研究结果表明，CYP2D6 和 ABCB1 G2677T 和 C3435T 可能是利培酮血浆浓度的有用决定因素，但这些关联与治疗反应和副作用相关的临床意义仍不清楚。
To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug-naive patients experiencing a first episode of psychosis.All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-restriction fragment length polymorphism analysis (for alleles *3,*4,*6) and long-distance PCR (for duplications and allele *5), while real-time PCR analysis was used for the ABCB1 G2677T/A and C3435T variants. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-performance liquid chromatography.The number of patients with the CYP2D6 wild type (wt)/wt, wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G, G/T and T/T variants was 29, 42 and 12, respectively; those with the 3435CC, C/T and T/T variants was 25, 37 and 21, respectively. The CYP2D6 genotype had a strong effect on the steady-state dose-corrected plasma levels (C/D) of risperidone, its 9-OH metabolite and the active moiety, while the ABCB1 2677 T/T and 3435 T/T genotypes has similarly strong effects on the active moiety C/D. The CYP2D6 poor metabolizers had a significantly higher risperidone C/D and active moiety C/D and lower 9-OH risperidone C/D. The ABCB1 3435 T allele and the ABCB1 2667 T-3435 T haplotype carriers were more frequent among subjects without extrapyramidal syndromes. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data.Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T may be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remain unclear.