Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data.

BACKGROUND

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.

METHODS

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.

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 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).

CONCLUSIONS

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.