Identification and Structural Characterization of Three New Metabolites of Bupropion in Humans

Sager, Jennifer E.; Choiniere, John R.; Chang, Justine; Stephenson‐Famy, Alyssa; Nelson, Wendel L.; Isoherranen, Nina

doi:10.1021/acsmedchemlett.6b00189

Cited by 20 publications

(49 citation statements)

References 14 publications

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“…The enantiomeric purity of R- and S-bupropion used in the experiments was confirmed to be >97.5% in all lots used using chiral HPLC. 4′-OH-bupropion, threo-4′-OH-hydrobupropion and erythro-4′-OH-hydrobupropion were synthesized as previously described [21]. α-OH-midazolam-d 4 was purchased from Cerilliant (Round Rock, TX) and dextromethorphan, dextrorphan, and Krebs-Henseleit buffer from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…The secondary antibody, IRDye 680 (anti-mouse; product #925-68070) was obtained from LiCor, Inc. (Lincoln, NE). Human plasma samples for measurement of steady state bupropion and metabolite concentrations were obtained from a previously described clinical study [21]. The study was approved by the University of Washington institutional review board.…”

Section: Methodsmentioning

confidence: 99%

“…The concentrations of bupropion and its metabolites and stereoisomers as applicable were determined using an LC/MS/MS system consisting of an AB-Sciex API 4500 triple quadrupole mass spectrometer (AB Sciex, Foster City, CA) coupled with an LC-20AD ultra-fast liquid chromatography system (Shimadzu Co., Kyoto, Japan) as previously described [19,21]. The turbo ion spray interface was operated in positive ion mode and bupropion and its metabolites were detected at mass transitions ( m / z ): 240→184 (bupropion), 249→189 (bupropion-d 9 ), 256→238 (OH-bupropion), 262→244 (OH-bupropion-d 6 ), 242→168 (threo- and erythrohydrobupropion), 251→168 (threohydrobupropion-d 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…The turbo ion spray interface was operated in positive ion mode and bupropion and its metabolites were detected at mass transitions ( m / z ): 240→184 (bupropion), 249→189 (bupropion-d 9 ), 256→238 (OH-bupropion), 262→244 (OH-bupropion-d 6 ), 242→168 (threo- and erythrohydrobupropion), 251→168 (threohydrobupropion-d 9 ). Bupropion and its metabolites in incubations and protein binding assays were separated as previously described [21] using an Agilent (Santa Clara, CA) ZORBAX XDB-C18 column (50x2.1 mm, 5 μm), while for cell media samples bupropion, OH-bupropion, threohydrobupropion, erythrohydrobupropion were separated using an Agilent (Santa Clara, CA) ZORBAX XDB-C18 column (150×4.6 mm, 5 μm) as previously described [21]. For analysis of HepG2 cell media and plated hepatocyte media, 100 μL of 3:1 acetonitrile:methanol was added to 100 μL of media.…”

Section: Methodsmentioning

confidence: 99%

“…It is also possible that additional metabolites of bupropion that exist in humans contribute to CYP2D6 inhibition in vivo. Recently, three new metabolites of bupropion, 4′OH-bupropion, threo-4′OH-hydrobupropion and erythro-4′OH-hydrobupropion were identified and characterized [19,21]. Although the circulating concentrations of these metabolites are much lower than those of bupropion, it is possible that they are present in the liver at sufficient concentrations to contribute to CYP2D6 inhibition.…”

Section: Introductionmentioning

confidence: 99%

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In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation

Sager

Tripathy

Price

et al. 2017

Biochemical Pharmacology

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Bupropion is a widely used antidepressant and smoking cessation aid and a strong inhibitor of CYP2D6 in vivo. Bupropion is administered as a racemic mixture of R- and S-bupropion and has stereoselective pharmacokinetics. Four primary metabolites of bupropion, threo- and erythrohydrobupropion and R,R- and S,S-OH-bupropion, circulate at higher concentrations than the parent drug and are believed to contribute to the efficacy and side effects of bupropion as well as to the CYP2D6 inhibition. However, bupropion and its metabolites are only weak inhibitors of CYP2D6 in vitro, and the magnitude of the in vivo drug-drug interactions (DDI) caused by bupropion cannot be explained by the in vitro data even when CYP2D6 inhibition by the metabolites is accounted for. The aim of this study was to quantitatively explain the in vivo CYP2D6 DDI magnitude by in vitro DDI data. Bupropion and its metabolites were found to inhibit CYP2D6 stereoselectively with up to 10-fold difference in inhibition potency between enantiomers. However, the reversible inhibition or active uptake into hepatocytes did not explain the in vivo DDIs. In HepG2 cells and in plated human hepatocytes bupropion and its metabolites were found to significantly downregulate CYP2D6 mRNA in a concentration dependent manner. The in vivo DDI was quantitatively predicted by significant down-regulation of CYP2D6 mRNA and reversible inhibition of CYP2D6 by bupropion and its metabolites. This study is the first example of a clinical DDI resulting from CYP down-regulation and first demonstration of a CYP2D6 interaction resulting from transcriptional regulation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation

Sager

Tripathy

Price

et al. 2017

Biochemical Pharmacology

Self Cite

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Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

Kharasch

Crafford

2018

Clin Pharma and Therapeutics

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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.

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

Kharasch

Neiner

Kraus

et al. 2020

Clin Pharma and Therapeutics

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The antidepressant bupropion is stereoselectively metabolized and metabolite enantiomers have differential pharmacologic effects, but steady-state enantiomeric disposition is unknown. Controversy persists about bupropion XL 300 mg generic equivalence to brand product, and whether generics might have different stereoselective disposition leading to enantiomeric non-bioequivalence and, thus, clinical nonequivalence. This preplanned follow-on analysis of a prospective, randomized, double-blinded, crossover study of brand and 3 generic bupropion XL 300 mg products measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations and evaluated bioequivalence and pharmacokinetics. Steady-state plasma and urine bupropion disposition was markedly stereoselective, with up to 40-fold differences in plasma concentrations of the active metabolite S,S-hydroxybupropion vs. R,R,-hydroxybupropion. Urine metabolite glucuronides were prominent, but glucuronidation was metabolite-specific and enantioselective. There were no differences between any generic and brand, or between generics, in plasma enantiomer concentrations of bupropion or the major metabolites. All generic products satisfied formal bioequivalence criteria (peak plasma concentration (C max) and area under the plasma concentration-time curve over 24 hours (AUC 0-24)) using enantiomers for bupropion as well as for metabolites, and generics were comparable to each other, and were considered bioequivalent, based on enantiomeric analysis. Enantiomeric bioequivalence explains the previously observed therapeutic equivalence of bupropion generics and brand in treating major depression. These results have important implications for understanding the clinical therapeutic effects of bupropion based on complex and stereoselective metabolism.

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Identification and Structural Characterization of Three New Metabolites of Bupropion in Humans

Cited by 20 publications

References 14 publications

In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation

In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

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

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