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Identification and Structural Characterization of Three New Metabolites of Bupropion in Humans Jennifer E Sager, John R. Choiniere, Justine Chang, Alyssa Stephenson-Famy, Wendel L. Nelson, and Nina Isoherranen ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00189 • Publication Date (Web): 17 Jun 2016 Downloaded from http://pubs.acs.org on June 20, 2016
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ACS Medicinal Chemistry Letters
Identification and Structural Characterization of Three New Metabolites of Bupropion in Humans Jennifer E. Sager,1 John R. Choiniere,1 Justine Chang2, Alyssa Stephenson-Famy2, Wendel L. Nelson,3 *Nina Isoherranen1 Department of Pharmaceutics1, Obstetrics and Gynecology2 and Medicinal Chemistry3, University of Washington, Seattle, Washington, USA KEYWORDS: Bupropion, structural characterization, metabolites, aromatic hydroxylation. ABSTRACT: Bupropion is a widely used antidepressant and the recommended CYP2B6 probe drug. However, current understanding of bupropion elimination pathways is limited. Bupropion has three active circulating metabolites, OH-bupropion, threohydrobupropion and erythrohydrobupropion, but together with bupropion these metabolites and their conjugates in urine represent only 23% of the dose, and the majority of the elimination pathways of bupropion result in uncharacterized metabolites. The aim of this study was to determine the structures of the uncharacterized bupropion metabolites using human clinical samples and in vitro incubations. Three new metabolites, 4’-OH-bupropion, erythro-4’-OH-hydrobupropion and threo-4’-OH-hydrobupropion were detected in human liver microsome incubations and were isolated from human urine. The structures of the metabolites were confirmed via comparison of UV absorbance, NMR spectra and mass spectral data to those of the synthesized standards. In total, these metabolites represented 24% of the drug related material excreted in urine.
Bupropion is a norepinephrine and dopamine reuptake inhibitor approved as an antidepressant1 and for smoking cessation2 and weight loss therapy.3 It is also the preferred sensitive in vivo CYP2B6 probe substrate recommended by the FDA.4 Yet, despite its numerous clinical and research applications, the factors contributing to the observed inter- and intraindividual variability in bupropion disposition and in its safety and efficacy are poorly understood.5–8
Figure 1. Bupropion and its active metabolites. Red arrows indicate potential additional hydroxylation sites
In vivo, bupropion undergoes extensive metabolism, with HO
4’-hydroxybupropion; M1 Cl
Cl
OH
HO
O
>
Bupropion
>
1 2 3 4 5 6 7
H N
Cl
Hydroxybupropion
OH NH
NH
> ACS Paragon Plus Environment HO Cl Threo/erythrohydrobupropion
Cl 4’-hydroxythreo/erythrohydrobupropion; M4, M6
