Enantiomeric Determination of the Phenylmorpholinol Metabolite of Bupropion in Human Plasma Using Coupled Achiral-Chiral Liquid Chromatography

Suckow, Raymond F.; Zhang, Ming F.; Cooper, Thomas B.

doi:10.1002/(sici)1099-0801(199705)11:3<174::aid-bmc681>3.0.co;2-e

Cited by 53 publications

(45 citation statements)

References 12 publications

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“…An additional chiral center is created when the hydroxyl intermediate spontaneously cyclizes to morpholinol and after reduction, potentially generating multiple diastereomers with unique disposition and effect profiles. Limited BUP and OHBUP data support striking stereoselective differences in their disposition (Suckow et al, 1997;Xu et al, 2007;Kharasch et al, 2008) and/or effect (Bondarev et al, 2003;Damaj et al, 2004;Carroll et al, 2014). This marked stereoselectivity is not fully explained by CYP2B6 alone and other mechanisms appear important (Gufford et al, 2016).…”

Section: Introductionsupporting

confidence: 84%

“…Although four stereoisomers are expected, only two trans-diastereomers, SS-and RR-OHBUP, were detected in plasma and when synthesized de novo (Suckow et al, 1997;Carroll et al, 2010Carroll et al, , 2014. These data are consistent with the suggestion that steric hindrance reduces cyclization to the cis-diastereomers, (2R,3S)-and (2S,3R)-OHBUP, and favors the thermodynamically more stable trans-isomers .…”

Section: Chiral Pharmacokinetics Of Bupropion and Metabolitesmentioning

confidence: 99%

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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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Section: Introductionsupporting

confidence: 84%

Section: Chiral Pharmacokinetics Of Bupropion and Metabolitesmentioning

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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“…Elevated hydroxybupropion plasma exposure is associated with improved bupropion treatment outcomes in depression (Laib et al, 2014) and smoking cessation (Zhu et al, 2012); however, hydroxybupropion plasma exposure varied widely among patients and is only partially explained by CYP2B6 genetic variation (Benowitz et al, 2013). Bupropion hydroxylation creates an additional chiral center, and two diastereomers [(2R,3R)-and (2S,3S)-hydroxybupropion] have been quantified in human plasma (Suckow et al, 1997;Coles and Kharasch, 2007;Xu et al, 2007). Wheres plasma exposure of (2R,3R)-hydroxybupropion is .20-fold higher than (2S,3S)-hydroxybupropion , some pharmacologic activity of bupropion may reside in (2S,3S)-hydroxybupropion (Bondarev et al, 2003;Damaj et al, 2004;Hansard et al, 2011).…”

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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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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“…Also, several studies including chiral separations of BUP and HBUP enantiomers were described [16][17][18] . Using Cooper's method, BUP stability in human plasma has been reported 19 .…”

Section: Research Articlementioning

confidence: 99%

Adsorptive Stripping Voltammetric Determination of Bupropion in Pharmaceuticals

2017

Chem Sci Trans

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Electrochemical studies of bupropion by voltammetric techniques were carried out. The bupropion gave one well-defined reduction peak at -1.2 to -1.3V vs. Ag/AgCl electrode in Britton Robinson buffer BR of pH 9. Under optimized conditions, a linear response was obtained between 1.0x10 -6 M to 5.6x10 -6 M in aqueous media for square wave and differential pulse cathodic adsorptive stripping voltammetric techniques. The electrochemical process was diffusion controlled. The value of limit of detection (LOD) are 1.28x10

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Enantiomeric Determination of the Phenylmorpholinol Metabolite of Bupropion in Human Plasma Using Coupled Achiral-Chiral Liquid Chromatography

Cited by 53 publications

References 12 publications

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

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

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Adsorptive Stripping Voltammetric Determination of Bupropion in Pharmaceuticals

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