Jerling M, Dahl M L, Aberg-Wistedt A, Liljenberg B, Landell N E, Bertilsson L, Sjöqvist F
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Sweden.
Clin Pharmacol Ther. 1996 Apr;59(4):423-8. doi: 10.1016/S0009-9236(96)90111-3.
Most antidepressant and neuroleptic agents are metabolized by the polymorphic cytochrome P450 enzyme CYP2D6. This study evaluates the importance of the CYP2D6 genotype for the disposition of the neuroleptic agents perphenazine and zuclopenthixol.
Patients treated with neuroleptic agents (n = 36) were studied prospectively with regard to CYP2D6 genotype and neuroleptic plasma concentration during oral treatment. Because no patient provided enough samples for individual kinetic modeling, a bayesian approach was used for determination of the clearance. Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data (n = 113) by use of a nonparametric approach.
The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression). The difference in clearance between homozygous extensive metabolizers and poor metabolizers was threefold for perphenazine and twofold for zuclopenthixol.
The results show that the genotype for CYP2D6 is closely related to the oral clearances of perphenazine and zuclopenthixol. If this finding can be confirmed in a larger population, genotyping may become an important tool for the dosing of these two neuroleptic agents.
大多数抗抑郁药和抗精神病药由多态性细胞色素P450酶CYP2D6代谢。本研究评估CYP2D6基因型对抗精神病药奋乃静和氯噻吨处置的重要性。
对接受抗精神病药治疗的患者（n = 36）进行前瞻性研究，观察口服治疗期间的CYP2D6基因型和抗精神病药血浆浓度。由于没有患者提供足够的样本进行个体动力学建模，因此采用贝叶斯方法来确定清除率。通过非参数方法从回顾性治疗药物监测数据（n = 113）中收集该程序的群体动力学参数。
CYP2D6基因型显著预测了奋乃静和氯噻吨的口服清除率（多元回归分析，p < 0.01）。纯合子广泛代谢者与代谢不良者之间的清除率差异，奋乃静为三倍，氯噻吨为两倍。
结果表明，CYP2D6基因型与奋乃静和氯噻吨的口服清除率密切相关。如果这一发现能在更大规模人群中得到证实，基因分型可能成为这两种抗精神病药给药的重要工具。
