Metabolism of Bupropion by Carbonyl Reductases in Liver and Intestine

Connarn, Jamie; Zhang, Xinyuan; Babiskin, Andrew; Sun, Duxin

doi:10.1124/dmd.115.063107

Cited by 33 publications

(45 citation statements)

References 34 publications

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“…Reduction of the keto group by 11b-hydroxysteroid dehydrogenase type 1 and other carbonyl reductases (Molnari and Myers, 2012;Meyer et al, 2013;Skarydova et al, 2014;Connarn et al, 2015) appears to favor formation of threo-hydrobupropion (Benowitz et al, 2013). Although this reduction creates an additional chiral center, potentially generating two distinct threo-hydrobupropion and two erythro-hydrobupropion diastereomers, data describing stereoselective elimination pathways and effect are lacking.…”

Section: Introductionmentioning

confidence: 99%

“…In vitro (Skarydova et al, 2014;Connarn et al, 2015) and in vivo (Benowitz et al, 2013) studies suggest that bupropion reduction to form two hydrobupropion metabolites is the major mechanism of bupropion clearance. Reduction of the keto group by 11b-hydroxysteroid dehydrogenase type 1 and other carbonyl reductases (Molnari and Myers, 2012;Meyer et al, 2013;Skarydova et al, 2014;Connarn et al, 2015) appears to favor formation of threo-hydrobupropion (Benowitz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Gufford

Metzger

et al. 2016

Drug Metabolism and Disposition

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Bupropion is a widely used antidepressant and smoking cessation aid in addition to being one of two US Food and Drug Administration-recommended probe substrates for evaluation of cytochrome P450 2B6 activity. Racemic bupropion undergoes oxidative and reductive metabolism, producing a complex profile of pharmacologically active metabolites with relatively little known about the mechanisms underlying their elimination. A liquid chromatography-tandem mass spectrometry assay was developed to simultaneously separate and detect glucuronide metabolites of (R,R)-and (S,S)-hydroxybupropion, (R,R)-and (S,S)-hydrobupropion (threo) and (S,R)-and (R,S)-hydrobupropion (erythro), in human urine and liver subcellular fractions to begin exploring mechanisms underlying enantioselective metabolism and elimination of bupropion metabolites. Human liver microsomal data revealed marked glucuronidation stereoselectivity [Cl int , 11.4 versus 4.3 ml/min per milligram for the formation of (R,R)-and (S,S)-hydroxybupropion glucuronide; and Cl max , 7.7 versus 1.1 ml/min per milligram for the formation of (R,R)-and (S,S)-hydrobupropion glucuronide], in concurrence with observed enantioselective urinary elimination of bupropion glucuronide conjugates. Approximately 10% of the administered bupropion dose was recovered in the urine as metabolites with glucuronide metabolites, accounting for approximately 40%, 15%, and 7% of the total excreted hydroxybupropion, erythrohydrobupropion, and threo-hydrobupropion, respectively. Elimination pathways were further characterized using an expressed UDP-glucuronosyl transferase (UGT) panel with bupropion enantiomers (both individual and racemic) as substrates. UGT2B7 catalyzed the stereoselective formation of glucuronides of hydroxybupropion, (S,S)-hydrobupropion, (S,R)-and (R,S)-hydrobupropion; UGT1A9 catalyzed the formation of (R,R)-hydrobupropion glucuronide. These data systematically describe the metabolic pathways underlying bupropion metabolite disposition and significantly expand our knowledge of potential contributors to the interindividual and intraindividual variability in therapeutic and toxic effects of bupropion in humans.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Gufford

Metzger

et al. 2016

Drug Metabolism and Disposition

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“…Numerous BUP metabolites have been identified (Welch et al, 1987;Petsalo et al, 2007;Gufford et al, 2016), but OHBUP, threohydrobupropion (THRHBUP), and erythrohydrobupropion (ERYHBUP) are of primary interest to understand BUP's effect and DDIs. BUP is 4-hydroxylated by CYP2B6 to OHBUP (Faucette et al, 2000;Hesse et al, 2000;Benowitz et al, 2013), whereas the reduction of BUP by 11b-hydroxysteroid dehydrogenase 1 and other carbonyl reductases (Meyer et al, 2013;Connarn et al, 2015) forms two amino alcohol stereoisomers, THRHBUP and ERYHBUP. OHBUP, THRHBUP, and ERYHBUP exhibit pharmacological activity in preclinical models (Martin et al, 1990;Bondarev et al, 2003;Damaj et al, 2004Damaj et al, , 2010 and may mediate BUP-induced seizures (Silverstone et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Masters

Gufford

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug-drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n 5 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography-tandem mass spectrometry assays. Time-dependent, elimination rate-limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and C max ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S-versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steadystate pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300-312 hours) from 185 to 37,447 nM×h] and elimination [terminal half-life of approximately 7-46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion's effects and DDIs with CYP2D6.

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“…( R,S )-bupropion undergoes stereoselective oxidative metabolism by cytochrome P450 2B6 (CYP2B6) to form (R,R) - and ( S,S )-hydroxybupropion [2]. Additionally, bupropion is stereoselectively reduced by carbonyl reductase(s) to form erythrohydrobupropion and threohydrobupropion [3]. The formation of threohydrobupropion is dependent on 11β-hydroxysteroid dehydrogenase 1 reduction of ( R )-bupropion in vitro [4]; however, the enzyme that forms erythrohydrobupropion has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a high-throughput stereoselective LC–MS/MS assay for bupropion, hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma

Teitelbaum

Flaker

Kharasch

2016

Journal of Chromatography B

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A stereoselective analytical method was developed and validated for the quantification of bupropion, and principle metabolites hydroxybupropion, erythrohydrobupropion and threohydrobupropion in human plasma. Separation of individual enantiomers (R)-bupropion, (S)-bupropion, (R,R)-hydroxybupropion, (S,S-hydroxybupropion), (1S,2S)-threohydrobupropion, (1R,2R)-threohydrobupropion, (1R,2S)-erythrohydrobupropion, and (1S,2R)-erythrohydrobupropion was achieved utilizing an α1-acid glycoprotein column within a 12-minute run time. Chromatograph separation was significantly influenced by mobile phase pH and variability between columns. Analytes were quantified by positive ion electrospray tandem mass spectrometry following plasma protein precipitation with 20% trichloroacetic acid. Identification of erythrohydrobupropion enantiomer peaks and threohydrobupropion enantiomer peaks was achieved by sodium borohydride reduction of enantiopure (R)- and (S)-bupropion. Initial assay validation and sensitivity determination was on AB Sciex 3200, 4000 QTRAP, and 6500 mass spectrometers. Accuracy and precision were within 15% for each analyte. The assay was fully validated over analyte-specific concentrations using an AB Sciex 3200 mass spectrometer. Intra- and inter-assay precision and accuracy were within 12% for each analyte. The limits of quantification for bupropion (R and S), hydroxybupropion (R,R and S,S), threohydrobupropion (1S,2S and 1R,2R), and erythrohydrobupropion (1R,2S and 1S,2R) were 0.5, 2, 1, and 1 ng/mL, respectively. All analytes were stable following freeze thaw cycles at −80°C and while stored at 4°C in the instrument autosampler. This method was applicable to clinical pharmacokinetic investigations of bupropion in patients. This is the first chromatographic method to resolve erythrohydrobupropion and threohydrobupropion enantiomers, and the first stereoselective LC-MS/MS assay to quantify bupropion, and principle metabolites hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma.

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Metabolism of Bupropion by Carbonyl Reductases in Liver and Intestine

Cited by 33 publications

References 34 publications

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Development and validation of a high-throughput stereoselective LC–MS/MS assay for bupropion, hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma

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