酒精使用障碍患者中CYP2D6和CYP3A同工酶的基因分型和表型分析：与氟哌啶醇血药浓度的相关性

Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration.

作者信息

Sychev Dmitry A, Zastrozhin Mikhail S, Miroshnichenko Igor I, Baymeeva Natalia V, Smirnov Valery V, Grishina Elena A, Ryzhikova Kristina A, Mirzaev Karin B, Markov Dmitry D, Skryabin Valentin Y, Snalina Nataliya E, Nosikova Polina G, Savchenko Ludmila M, Bryun Evgeny A

机构信息

出版信息

Drug Metab Pers Ther. 2017 Sep 26;32(3):129-136. doi: 10.1515/dmpt-2017-0021.

DOI:10.1515/dmpt-2017-0021

PMID:28787271

Abstract

BACKGROUND

Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder.

METHODS

The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-β-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-β-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS.

RESULTS

Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037].

CONCLUSIONS

The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

摘要

背景

氟哌啶醇用于治疗有酒精相关精神病体征的酒精使用障碍患者。氟哌啶醇治疗存在较高的药物不良反应（ADR）风险。在不同基因型患者中，存在相互矛盾的数据，其中包括编码氟哌啶醇生物转化系统元件的基因中的基因多态性对氟哌啶醇代谢率和血浆药物浓度比的影响。本研究的主要目的是调查CYP2D6和CYP3A5基因多态性对酒精使用障碍患者氟哌啶醇平衡浓度的影响。

方法

该研究纳入了69名患有酒精使用障碍的男性患者。使用等位基因特异性实时PCR进行基因分型。使用酶的内源性底物及其尿液代谢物的浓度，通过高效液相色谱-质谱联用（HPLC-MS）对CYP2D6和CYP3A进行表型分析[CYP2D6的6-羟基-1,2,3,4-四氢-β-咔啉（6-HO-THBC）与匹诺啉的比率以及CYP3A的6-β-羟基皮质醇与皮质醇的比率]。使用液相色谱-串联质谱（LC-MS-MS）测定血浆平衡浓度。