Bupropion is one of the most commonly used treatments for major depressive disorder, and it is also used for smoking cessation. There is concern about the bioequivalence and clinical effectiveness of various brand and generic oral bupropion formulations (Woodcock et al., 2012).
We read with interest the recent article by Gufford et al. (2016). Liquid chromatography–mass spectrometry was employed to identify the specific UDP-glucuronosyl transferase isoforms involved in the glucuronidation of threohydrobupropion and erythrohydrobupropion metabolites, which are formed by carbonyl reduction of bupropion. Additionally, UDP-glucuronosyl transferase enzyme kinetics was assessed by incubations of racemic parent aglycones (threohydrobupropion and erythrohydrobupropion) in human liver microsomes. In addition, following the administration of bupropion to healthy volunteers, glucuronide metabolites were quantified in urine, and their urinary excretion kinetics was evaluated.
We also read with interest the recent article by Masters et al. (2016). Healthy volunteers were administered oral immediate-release racemic bupropion, and the urinary excretion of the parent drug and metabolites was quantified by liquid chromatography–mass spectrometry. Single-dose pharmacokinetic parameters were determined and also used to predict steady-state disposition.
In both of the above articles, threohydrobupropion and erythrohydrobupropion glucuronide standards were purchased from Toronto Research Chemicals (TRC, Toronto, Canada) for structural identification and quantification of glucuronide metabolites. Compounds were D448175 (S,S)-dihydrobupropion β-D-glucuronide, D448165 (R,R)-dihydrobupropion β-D-glucuronide, and D448655 racemic erythro-dihydrobupropion β-D-glucuronide.
Unfortunately, however, the glucuronide metabolite standards from TRC were incorrectly labeled with regard to stereochemistry. The mislabeling was recently discovered (Teitelbaum et al., 2016). Through a combination of β-glucuronidase hydrolysis experiments and chemical oxidation of the resulting aglycone, correct structures were identified (Teitelbaum et al., 2016). TRC product D448175 (S,S)-dihydrobupropion β-D-glucuronide [also referred to as (1S,2S)-threohydrobupropion β-D-glucuronide] is really (1R,2R) threohydrobupropion β-D-glucuronide. TRC product D448165 (R,R)-dihydrobupropion β-D-glucuronide [also referred to as (1R,2R)-threohydrobupropion β-D-glucuronide] is really (1S,2S) threohydrobupropion β-D-glucuronide. And rac-erythrodihydrobupropion β-D-glucuronide (also referred to as rac-erythrohydrobupropion β-D-glucuronide) is really (1R,2S)-erythrohydrobupropion β-D-glucuronide.
As a result of the vendor mislabeling, the article by Gufford et al. (2016) and the article by Masters et al. (2016) thus also unfortunately misidentified the threohydrobupropion and erythrohydrobupropion glucuronide metabolites of bupropion. We bring this to the attention of the authors and readers, and we suggest a re-evaluation and publication of a correction of the data with regard to the identification and quantification of glucuronide metabolites from the in vitro and in vivo studies and any revised interpretation and discussion as needed.
Abbreviation
- TRC
Toronto Research Chemicals
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Teitelbaum, Kharasch.
Footnotes
This work was supported by National Institutes of Health [Grants R01-DA14211 and U01-FD004899 (to E.D.K.) and 5T32DA007261 (to A.M.T.)].
No author has any conflict of interest.
References
- 1.Woodcock J, Khan M, Yu LX. (2012) Withdrawal of generic budeprion for nonbioequivalence. N Engl J Med 367:2463–2465. [DOI] [PubMed] [Google Scholar]
- 2.Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z. (2016) Stereoselective glucuronidation of bupropion metabolites in vitro and in vivo. Drug Metab Dispos 44:544–553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z. (2016) Chiral plasma pharmacokinetics and urinary excretion of bupropion and metabolites in healthy volunteers. J Pharmacol Exp Ther 358:230–238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Teitelbaum AM, Flaker AM, Kharasch ED. (2016) Development, validation and application of a comprehensive stereoselective LC/MS-MS assay for bupropion and oxidative, reductive, and glucuronide metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 1027:239–253. [DOI] [PMC free article] [PubMed] [Google Scholar]