Høiseth Gudrun, Haslemo Tore, Uthus Linda H, Molden Espen
*Center for Psychopharmacology, Diakonhjemmet Hospital; †Division of Forensic Sciences, Norwegian Institute of Public Health; and ‡Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
Ther Drug Monit. 2015 Oct;37(5):589-93. doi: 10.1097/FTD.0000000000000183.
The clinical effect of bupropion is mediated by its active metabolite hydroxybupropion. Previous studies have reported conflicting impact of the CYP2B66 variant allele on the formation of hydroxybupropion from bupropion. The aim of this study was to clarify the effect of CYP2B66 and secondarily CYP2D6 genotype on steady-state serum concentrations of bupropion and hydroxybupropion in a large population of psychiatric patients.
Retrospective information about dose-adjusted serum concentrations (C/D ratios) of bupropion and hydroxybupropion, CYP2B6 genotype (ie, data on the 2B66 polymorphisms 516G>T and 785A>G) and CYP2D6 genotype, was obtained from a therapeutic drug monitoring database (n = 132 patients). C/D ratios of bupropion and hydroxybupropion, and metabolic ratios, were compared between CYP2B6 genotype subgroups by multivariate mixed-model analyses (2B61/*1 was defined as control group). In the analyses, CYP2D6 genotype was also included as a covariate.
Homozygous 2B6*6 carriers (n = 7) had significantly lower C/D ratios of hydroxybupropion compared with controls (n = 79), that is, estimated mean 5.8 versus 13.0 nmol·L·mg (P < 0.001). C/D ratio of hydroxybupropion in heterozygous 6 carriers (12.1 nmol·L·mg; n = 46) did not significantly differ compared with controls (P = 0.32). The hydroxybupropion/bupropion metabolic ratios in heterozygous and homozygous 2B66 carriers were significantly lower than in controls (P = 0.001 and P < 0.001, respectively). CYP2D6 genotype did not significantly alter the hydroxybupropion C/D ratio, but higher bupropion values were observed in poor versus extensive CYP2D6 metabolizers (P = 0.020).
This study shows that the CYP2B66 variant allele is associated with significantly reduced formation of the active bupropion metabolite in psychiatric patients. Our findings suggest that dose-adjusted serum concentrations of hydroxybupropion at steady state is approximately halved in homozygous CYP2B66 carriers, which might imply risk of reduced clinical response in this patient subgroup. The CYP2D6 genotype does not affect hydroxybupropion concentrations and is therefore unlikely to impact bupropion treatment.
安非他酮的临床疗效由其活性代谢产物羟基安非他酮介导。既往研究报道了细胞色素P450 2B6（CYP2B6）6变异等位基因对安非他酮形成羟基安非他酮的影响存在矛盾。本研究的目的是阐明CYP2B66以及次要的细胞色素P450 2D6（CYP2D6）基因型对大量精神科患者中安非他酮和羟基安非他酮稳态血清浓度的影响。
从治疗药物监测数据库（n = 132例患者）中获取关于安非他酮和羟基安非他酮剂量调整后血清浓度（C/D比值）、CYP2B6基因型（即2B66多态性516G>T和785A>G的数据）以及CYP2D6基因型的回顾性信息。通过多变量混合模型分析比较CYP2B6基因型亚组之间安非他酮和羟基安非他酮的C/D比值以及代谢比值（将2B61/*1定义为对照组）。在分析中，CYP2D6基因型也作为协变量纳入。
与对照组（n = 79）相比，纯合2B66携带者（n = 7）的羟基安非他酮C/D比值显著更低，即估计均值分别为5.8和13.0 nmol·L·mg（P < 0.001）。杂合6携带者（n = 46）的羟基安非他酮C/D比值（12.1 nmol·L·mg）与对照组相比无显著差异（P = 0.32）。杂合和纯合2B6*6携带者的羟基安非他酮/安非他酮代谢比值显著低于对照组（分别为P = 0.001和P < 0.001）。CYP2D6基因型未显著改变羟基安非他酮C/D比值，但与CYP2D6代谢良好者相比，代谢不良者的安非他酮值更高（P = 0.020）。
本研究表明，CYP2B66变异等位基因与精神科患者中活性安非他酮代谢产物的形成显著减少相关。我们的研究结果表明，纯合CYP2B66携带者中稳态时羟基安非他酮的剂量调整后血清浓度大约减半，这可能意味着该患者亚组临床反应降低的风险。CYP2D6基因型不影响羟基安非他酮浓度，因此不太可能影响安非他酮治疗。
