The impact of the CYP2D6 polymorphism on haloperidol pharmacoldnetics and on the outcome of haloperidol treatment
The impact of the CYP2D6 polymorphism on haloperidol pharmacoldnetics and on the outcome of haloperidol treatment
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DOI：
10.1067/mcp.2002.127494
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发表时间：
2002-10-01
影响因子：
6.7
通讯作者：
Roots, I
中科院分区：
文献类型：
--
作者：
Brockmöller, J;Kirchheiner, J;Roots, I
目的：基因多态性酶细胞色素 P450 (CYP) 2D6 有助于抗精神病药物氟哌啶醇的生物转化。在 172 名未经选择的患有急性精神病症状的精神病住院患者中，前瞻性评估了多态性对氟哌啶醇药代动力学、不良事件和疗效的影响。入院后第 3、14 和 28 天，对接受临床调整剂量的患者的氟哌啶醇和减量氟哌啶醇的血清谷水平进行分析。通过标准化评分量表评估锥体外系症状等不良事件。通过记录阳性和阴性精神分裂症症状的变化来记录疗效。这些参数与通过聚合酶链式反应分析等位基因*1至*15和*17确定的CTP2D6基因型相关。结果：血清浓度显示出广泛的个体差异。氟哌啶醇谷水平和氟哌啶醇总清除率降低与活性 CYP2D6 基因的数量显着相关。此外，体重和吸烟对氟哌啶醇动力学有显着影响，而年龄、性别和药物治疗仅显示轻微影响。 CYP2D6 底物代谢不良者的假性帕金森病评分显着较高。另一方面，随着活性 CYP2D6 基因数量的增加，治疗效果有降低的趋势。结论。对于 CYP2D6 底物代谢速度极慢和极快的患者，应避免使用氟哌啶醇治疗。基因分型和血液浓度测量只能解释一小部分不良事件；大约需要对 20 名患者进行基因分型才能使 1 名患者获得显着获益。有趣的是，基因分型至少与测量的药物浓度一样能很好地预测不良事件。
Objectives: The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated tinder naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms.Methods. Serum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission. Adverse events such as extrapyramidal symptoms were assessed by standardized rating scales. Efficacy was documented by recording the change in positive and negative schizophrenic symptoms. These parameters were correlated with the CTP2D6 genotype determined by polymerase chain reaction analysis for alleles * 1 to * 15 and * 17.Results: The serum concentrations showed wide interindividual variation. Reduced haloperidol trough levels and haloperidol total clearance correlated significantly with the number of active CYP2D6 genes. In addition, body weight and smoking had significant effects on haloperidol kinetics, whereas age, gender, and comedication showed only slight effects. The ratings for pseudoparkinsonism were significantly higher in poor metabolizers of substrates of CYP2D6. On the other hand, there was a trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes.Conclusions. Treatment with haloperidol should be avoided in extremely slow and extremely rapid metabolizers of CYP2D6 substrates. Both genotyping and blood concentration measurement explained only a fraction of the adverse events; about 20 patients would have to be genotyped to achieve a significant benefit in 1 patient. It is interesting that genotyping was at least as good a predictor of adverse events as the measured drug concentrations.