Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

Abstract

Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes.

Stereoselective Bupropion Hydroxylation by Cytochrome P450 CYP2B6 and Cytochrome P450 Oxidoreductase Genetic Variants

“…In vitro-in vivo concordance is less consistent for CYP2B6*4 than for decreased metabolism polymorphisms, which may be influenced by the rarity of CYP2B6*4. CYP2B6.4 had minimally increased bupropion hydroxylation in vitro, and numerically but not significantly higher plasma hydroxybupropion/bupropion AUC ratios in CYP2B6*4 hererozygotes for the racemate (Kirchheiner et al, 2003;Zhu et al, 2012;Ma et al, 2018;Kharasch and Crafford, 2019) and enantiomers (Kharasch and Crafford, 2019). Based on these patterns, and the present in vitro results, it could be expected that other CYP2B6 polymorphisms coding for diminished (*5, *6, *7, *9, *19, *26) or defective (*16) in vitro bupropion hydroxylation might result in diminished in vivo bupropion hydroxylation.…”

“…There is high concordance between POR and CYP2B6 genetic variant effects on bupropion metabolism in vitro and in vivo. POR*28 had little effect on bupropion hydroxylation in vitro, or in vivo, based on plasma hydroxybupropion/bupropion area under the curve (AUC) ratios and urine hydroxybupropion formation clearance (Gao et al, 2016;Lv et al, 2016;Kharasch and Crafford, 2019).…”

“…Plasma racemic hydroxybupropion/bupropion AUC ratios after single-dose bupropion were lower in CYP2B6*6 carriers than noncarriers (Chung et al, 2011), lower in CYP2B6*6/*6 and CYP2B6*1/*6 versus CYP2B6*1/*1 genotypes (Gao et al, 2016;Lv et al, 2016), and hydroxybupropion concentrations were lower in CYP2B6*6 heterozygotes than wild-types (Ma et al, 2018). Assessed stereoselectively, plasma AUC ratios and urine hydroxybupropion formation clearances for both bupropion enantiomers, after a single bupropion dose, were lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes (Kharasch and Crafford, 2019). At steady-state, plasma racemic hydroxybupropion/bupropion AUC ratios in CYP2B6 slow (*6/*6, *18/*18 genotypes) and intermediate (*6 and *18 heterozygotes) metabolizers were 34% and 54%, respectively, of those in normal metabolizers (*1/*1, *1/*4, *1/*5, *1/*22, *22/*22), and hydroxybupropion plasma concentrations were 40% and 20% lower in slow and intermediate than normal metabolizers (Zhu et al, 2012).…”

Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

“…15 Bupropion metabolism is stereoselective in vitro, [16][17][18] and single-dose studies in healthy volunteers have shown that it is stereoselective in vivo. [19][20][21][22][23][24] Plasma exposures are 2-fold to 6-fold higher for R-bupropion than S-bupropion, S-bupropion apparent oral clearance exceeds that of R-bupropion, and R,R-hydroxybupropion exposures are 20-fold to 65-fold higher than S,S-hydroxybupropion. 20,21,24,25 Stereoselective disposition is important, because bupropion antidepressant and antismoking effects are attributed to S,S-hydroxybupropion rather than R,Rhydroxybupropion, despite the lower plasma concentrations.…”

“…[19][20][21][22][23][24] Plasma exposures are 2-fold to 6-fold higher for R-bupropion than S-bupropion, S-bupropion apparent oral clearance exceeds that of R-bupropion, and R,R-hydroxybupropion exposures are 20-fold to 65-fold higher than S,S-hydroxybupropion. 20,21,24,25 Stereoselective disposition is important, because bupropion antidepressant and antismoking effects are attributed to S,S-hydroxybupropion rather than R,Rhydroxybupropion, despite the lower plasma concentrations. [26][27][28][29] Although the vast majority of studies have traditionally evaluated plasma concentrations of racemic hydroxybupropion, Figure 1 Bupropion metabolism.…”