Association of CYP2B6 genetic polymorphisms with bupropion and hydroxybupropion exposure: A systematic review and meta‐analysis

Abstract

Introduction: Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme.Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6 genotype on the exposure of bupropion has not been quantified. Objectives:A systematic review and meta-analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotypedefined metabolizer phenotypes.Methods: MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration-time curve (AUC) of bupropion and/or HB in relation to CYP2B6 genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6 genotype or genotypedefined phenotype groups for bupropion exposure was calculated for each study and combined in a meta-analysis.Results: Eleven studies met the inclusion criteria for this systematic review, and 10 (including N = 413 participants) were included in the meta-analysis. All 10 studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in

Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine

“…BUP 4-hydroxylation is an important bioactivation pathway and a marker of CYP2B6 activity, but the fraction metabolized via 4hydroxylation is small. This is supported by the lack of meaningful effect of CYP2B6 strong inhibitors (Palovaara et al, 2003;Turpeinen et al, 2005) or slow metabolizer of CYP2B6 (Eum et al, 2022) on BUP systemic clearance. The present findings and recent data (Sager et al, 2016) suggest that BUP reduction to THBUP represents the major clearance mechanism of BUP in human liver.…”

Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers

“…The mechanism by which efavirenz causes large decrease in the exposure of BUP and its enantiomers is unlikely due to induction of CYP2B6 mediated BUP 4-hydroxylation as the fraction metabolized by CYP2B6 under basal conditions is small ( ∼21%) (Sager et al, 2016). This is further supported by the lack of meaningful effect of modulators of CYP2B6 on BUP systemic clearance despite their marked effect on OHBUP exposure (present data from the inhibition phase; (Eum et al, 2022)). Our recent data (Bamfo et al, 2022) and findings from other authors (Sager et al, 2016) support that BUP reduction, particularly to THBUP and SS-THBUP, represents the major clearance mechanism of BUP and its enantiomers in vitro.…”

Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall

“…Given the much higher concentration of HB, it is likely to contribute the majority of the pharmacologic activity of bupropion. In vivo pharmacokinetic studies have shown that CYP2B6 PMs (e.g., CYP2B6 * 6/* 6 ) have lower steady-state HB/bupropion metabolic ratios and HB concentrations compared to NMs [ 33 , 35 ], the latter of which was corroborated in a recent meta-analysis [ 36 ]. Lower HB concentrations in plasma have been associated with reduced response to bupropion for depression [ 37 ].…”

“…Case report evidence in a CYP2B6 PM taking bupropion illustrated a lack of efficacy with bupropion despite high doses [ 38 ]. Further, based on meta-analysis results showing a 33% decrease of HB area under the plasma drug concentration-time curve in CYP2B6 PMs, the investigators estimated that this reflected an approximately 50% higher bupropion dose requirement to achieve similar HB exposure as in NMs [ 36 ]. Recall that the patient in this case was a CYP2B6 PM and therefore was expected to exhibit less conversion to HB.…”

“…A preemptive PGx test may have better informed initial recommendations for MDD/GAD; had CYP2B6 genotype been assessed preemptively, the medical team could have recognized that the patient may have an increased risk of inefficacy with bupropion and selected an alternative agent. However, given the literature for CYP2B6 and bupropion is predominantly limited to pharmacokinetic studies and case reports [ 33 , 35 , 36 , 38 ], the provider might have been less inclined to accept such a recommendation.…”