Therapeutic drug monitoring · 2015
Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data.
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Høiseth Gudrun, Haslemo Tore, Uthus Linda H, Molden Espen
Аннотация
BACKGROUND: The clinical effect of bupropion is mediated by its active metabolite hydroxybupropion. Previous studies have reported conflicting impact of the CYP2B6*6 variant allele on the formation of hydroxybupropion from bupropion. The aim of this study was to clarify the effect of CYP2B6*6 and secondarily CYP2D6 genotype on steady-state serum concentrations of bupropion and hydroxybupropion in a large population of psychiatric patients.
METHODS: Retrospective information about dose-adjusted serum concentrations (C/D ratios) of bupropion and hydroxybupropion, CYP2B6 genotype (ie, data on the 2B6*6 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 (2B6*1/*1 was defined as control group). In the analyses, CYP2D6 genotype was also included as a covariate.
RESULTS: 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 2B6*6 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).
CONCLUSIONS: This study shows that the CYP2B6*6 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 CYP2B6*6 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.
METHODS: Retrospective information about dose-adjusted serum concentrations (C/D ratios) of bupropion and hydroxybupropion, CYP2B6 genotype (ie, data on the 2B6*6 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 (2B6*1/*1 was defined as control group). In the analyses, CYP2D6 genotype was also included as a covariate.
RESULTS: 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 2B6*6 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).
CONCLUSIONS: This study shows that the CYP2B6*6 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 CYP2B6*6 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.