Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion

Abstract

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.

Graphical abstract

Fig. 1.

Bupropion metabolism. Shown are oxidative, reductive, and glucuronide metabolites of R-bupropion and S-bupropion. Adapted from Kharasch et al. (Kharasch et al., 2020), which also shows structures.

Fig. 2.

Influence of CYP2B6 genotype on plasma bupropion disposition. Each data point is the mean ± S.D. Some S.D. are omitted for clarity. Numbers of subjects in each group are shown in Table 1.

Fig. 3.

Influence of CYP2B6 genotype on plasma bupropion disposition. Results are for CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6 genotypes only. Each data point is the mean ± S.D. Some S.D. are omitted for clarity.

Fig. 4.

Influence of the CYP2B6 516G>T single nucleotide variant on plasma bupropion disposition. Each data point is the mean ± S.D. Some S.D. are omitted for clarity.

Fig. 5.

Influence of CYP2C19 genotype on plasma bupropion disposition. Patients were grouped into normal, intermediate, poor, rapid, and ultrarapid metabolizer status. Each data point is the mean ± S.D. Some S.D. are omitted for clarity. Numbers of subjects in each group are shown in Table 1.

Fig. 6.

Influence of POR genotype on plasma bupropion disposition. Each data point is the mean ± S.D. Some S.D. are omitted for clarity. Numbers of subjects in each group are shown in Table 1. The first two columns of figures show the influence of POR*28. The last two columns of figures show the influence of the intron variant g.6593 A>G.