Skip to main content
SpringerLink
Log in

Comparison of In Vitro Stereoselective Metabolism of Bupropion in Human, Monkey, Rat, and Mouse Liver Microsomes

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Bupropion is an atypical antidepressant and smoking cessation aid associated with wide intersubject variability. This study compared the formation kinetics of three phase I metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion) in human, marmoset, rat, and mouse liver microsomes. The objective was to establish suitability and limitations  for subsequent use of nonclinical species to model bupropion central nervous system (CNS) disposition in humans.

Methods

Hepatic microsomal incubations were conducted separately for the R- and S-bupropion enantiomers, and the formation of enantiomer-specific metabolites was determined using LC-MS/MS. Intrinsic formation clearance (CLint) of metabolites across the four species was determined from the formation rate versus substrate concentration relationship.

Results

The total clearance of S-bupropion was higher than that of R-bupropion in monkey and human liver microsomes. The contribution of hydroxybupropion to the total racemic bupropion clearance was 38%, 62%, 17%, and 96% in human, monkey, rat, and mouse, respectively.  In the same species order, threohydrobupropion contributed 53%, 23%, 17%, and 3%, and erythrohydrobupropion contributed 9%, 14%, 66%, and 1.3%, respectively, to racemic bupropion clearance.

Conclusion

The results demonstrate that phase I metabolism in monkeys best approximates that observed in humans, and support the preferred use of this species to investigate possible pharmacokinetic factors that influence the CNS disposition of bupropion and contribute to its high intersubject variability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Adapted from [28]

Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fava M, et al. 15 years of clinical experience with bupropion HCL: from bupropion to bupropion SR to bupropion XL. Prim Care Compan J Clin Psychiatry. 2005;7(3):106–13.

    Article  Google Scholar 

  2. Ornellas T, Chavez B. Naltrexone SR/bupropion SR (Contrave): a new approach to weight loss in obese adults. Pharm Therapeut. 2011;36(5):255–62.

  3. Reimherr FW, et al. Bupropion SR in adults with ADHD: a short-term, placebo-controlled trial. Neuropsychiatr Dis Treatm. 2005;1(3):245–51.

    CAS  Google Scholar 

  4. Berigan TR. The many uses of bupropion and bupropion sustained release (SR) in adults. Prim Care Compan J Clin Psychiatry. 2002;4(1):30–2.

    Article  Google Scholar 

  5. Hamedi M, et al. Bupropion in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind study. Acta Medica Iranica. 2014:52(9):675–80.

  6. Wilens TE, et al. An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder. Biol Psychiatry 2003;54(1):9–16.

  7. Woodcock J, Khan M, Yu LX. Withdrawal of generic budeprion for nonbioequivalence. N Engl J Med. 2012;367(26):2463–5.

    Article  CAS  Google Scholar 

  8. Golden RN, et al. Bupropion in depression. II. The role of metabolites in clinical outcome. Arch Gen Psychiatry. 1988;45(2):145–9.

    Article  CAS  Google Scholar 

  9. Connarn JN, et al. Identification of non-reported bupropion metabolites in human plasma. Biopharm Drug Dispos. 2016;37(9):550–60.

    Article  CAS  Google Scholar 

  10. Hesse LM, et al. Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenet Genomics. 2004;14(4):225–38.

    Article  CAS  Google Scholar 

  11. Laizure SC, et al. Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose. Clin Pharmacol Ther. 1985;38(5):586–9.

    Article  CAS  Google Scholar 

  12. Zhu AZX, et al. CYP2B6 and bupropion’s smoking-cessation pharmacology: the role of hydroxybupropion. Clin Pharmacol Ther. 2012;92(6):771–7.

  13. Benowitz NL, et al. Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state. Pharmacogenet Genomics. 2013;23(3):135–41.

    Article  CAS  Google Scholar 

  14. Zhu AZX, et al. Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes. Drug Metab Dispos. 2014;42(11):1971–7.

    Article  Google Scholar 

  15. Connarn JN, et al. Pharmacokinetics and pharmacogenomics of bupropion in three different formulations with different release kinetics in healthy human volunteers. AAPS J. 2017;19(5):1513–22.

    Article  CAS  Google Scholar 

  16. Grandas F, López-Manzanares L. Bupropion-induced parkinsonism. Mov Disord. 2007;22(12):1830–1.

    Article  Google Scholar 

  17. Davidson J. Seizures and bupropion: a review. J Clin Psychopharmacol. 1990;10(1):60–2.

    Article  Google Scholar 

  18. Johnston JALC, Ascher JA, et al. A 102-center prospective study of seizure in association with bupropion. J Clin Psychiatry. 1991;52:450–6.

    CAS  PubMed  Google Scholar 

  19. Beyens M-N, et al. Serious adverse reactions of bupropion for smoking cessation: analysis of the French Pharmacovigilance Database from 2001 to 2004. Drug Saf. 2008;31(11):1017–26.

    Article  CAS  Google Scholar 

  20. Gufford BT, et al. Stereoselective glucuronidation of bupropion metabolites in vitro and in vivo. Drug Metab Dispos. 2016;44(4):544–53.

    Article  CAS  Google Scholar 

  21. Masters AR, et al. Chiral plasma pharmacokinetics and urinary excretion of bupropion and metabolites in healthy volunteers. J Pharmacol Exp Ther. 2016;358(2):230–8.

    Article  CAS  Google Scholar 

  22. Kharasch ED, Mitchell D, Coles R. Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activity. J Clin Pharmacol. 2008;48(4):464–74.

    Article  CAS  Google Scholar 

  23. Coles R, Kharasch ED. Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomes. Pharm Res. 2008;25(6):1405–11.

    Article  CAS  Google Scholar 

  24. Suckow RF, et al. Pharmacokinetics of bupropion and metabolites in plasma and brain of rats, mice, and guinea pigs. Drug Metab Dispos. 1986;14(6):692–7.

    CAS  PubMed  Google Scholar 

  25. Damaj MI, et al. Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. Mol Pharmacol. 2004;66(3):675.

    Article  CAS  Google Scholar 

  26. Damaj MI, et al. Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice. J Pharmacol Experim Therapeut. 2010;334(3):1087–95.

    Article  CAS  Google Scholar 

  27. Carroll FI, et al. Chapter 5: Bupropion and bupropion analogs as treatments for CNS disorders. In: Linda PD, editor. Advances in pharmacology. New York: Academic; 2014. p. 177–216.

  28. Sager JE, Price LSL, Isoherranen N. Stereoselective metabolism of bupropion to OH-bupropion, threohydrobupropion, erythrohydrobupropion, and 4′-OH-bupropion in vitro. Drug Metab Dispos. 2016;44(10):1709–19.

    Article  CAS  Google Scholar 

  29. Silverstone PH, et al. Convulsive liability of bupropion hydrochloride metabolites in Swiss albino mice. Ann Gen Psychiatry. 2008;7:19.

    Article  Google Scholar 

  30. Skarydova L, et al. Deeper insight into the reducing biotransformation of bupropion in the human liver. Drug Metab Pharmacokinet. 2014;29(2):177–84.

    Article  CAS  Google Scholar 

  31. Swan GE, et al. Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics J. 2004;5:21.

    Article  Google Scholar 

  32. Spraggs CF, Dow D, Douglas C, McCarthy L, Manasco PK, Stubbins M, Roses AD. Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects. Pharmacogenet Genomics. 2005;15(12):883–9.

  33. Bondarev ML, et al. Behavioral and biochemical investigations of bupropion metabolites. Eur J Pharmacol. 2003;474(1):85–93.

    Article  CAS  Google Scholar 

  34. Grabus SD, Carroll FI, Damaj MI. Bupropion and its main metabolite reverse nicotine chronic tolerance in the mouse. Nicotine Tob Res. 2012;14(11):1356–61.

    Article  CAS  Google Scholar 

  35. Deveaugh-Geiss J, et al. GW320659 for the treatment of attention-deficit/hyperactivity disorder in children. J Am Acad Child Adolesc Psychiatry. 2002;41(8):914–20.

    Article  Google Scholar 

  36. Volkow ND, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiat. 2005;57(6):640–6.

    Article  CAS  Google Scholar 

  37. Ascher JA, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395–401.

    CAS  PubMed  Google Scholar 

  38. Schroeder DH. Metabolism and kinetics of bupropion. J Clin Psychiatry. 1983;44(5 Pt 2):79–81.

  39. Martin P, et al. Antidepressant profile of bupropion and three metabolites in mice. Pharmacopsychiatry. 1990;23(04):187–94.

    Article  CAS  Google Scholar 

  40. Agarwal V, et al. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. PLoS One. 2008;3(6):e2337.

    Article  Google Scholar 

  41. Miksys S, Tyndale RF. The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics. Drug Metab Rev. 2004;36(2):313–33.

    Article  CAS  Google Scholar 

  42. Ravindranath V, Kommaddi RP, Pai HV. Unique cytochromes P450 in human brain: implication in disease pathogenesis. In: Riederer P, Reichmann H, Youdim MBH, Gerlach M, editors. Parkinson’s disease and related disorders. Vienna: Springer; 2006.

  43. Khokhar JY, Tyndale RF. Drug metabolism within the brain changes drug response: selective manipulation of brain CYP2B alters propofol effects. Neuropsychopharmacology. 2011;36(3):692–700.

    Article  CAS  Google Scholar 

  44. Ferguson CS, Tyndale RF. Cytochromes P450 in the brain: emerging evidence for biological significance. Trends Pharmacol Sci. 2011;32(12):708–14.

    Article  CAS  Google Scholar 

  45. Sharon M, Tyndale RF. Brain drug-metabolizing cytochrome P450 enzymes are active in vivo, demonstrated by mechanism-based enzyme inhibition. Neuropsychopharmacology. 2009;34(3):634–40.

    Article  Google Scholar 

  46. Toselli F, Dodd PR, Gillam EMJ. Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs. Drug Metab Rev. 2016;48(3):379–404.

    Article  CAS  Google Scholar 

  47. Khokhar JY, Miksys SL, Tyndale RF. Rat brain CYP2B induction by nicotine is persistent and does not involve nicotinic acetylcholine receptors. Brain Res. 2010;1348:1–9.

    Article  CAS  Google Scholar 

  48. Cremers TIFH, et al. Development of a rat plasma and brain extracellular fluid pharmacokinetic model for bupropion and hydroxybupropion based on microdialysis sampling, and application to predict human brain concentrations. Drug Metab Dispos. 2016;44(5):624–33.

    Article  CAS  Google Scholar 

  49. Welch RM, Lai AA, Schroeder DH. Pharmacological significance of the species differences in bupropion metabolism. Xenobiotica. 1987;17(3):287–98.

    Article  CAS  Google Scholar 

  50. Meyer A, et al. Formation of threohydrobupropion from bupropion is dependent on 11β-hydroxysteroid dehydrogenase 1. Drug Metab Dispos. 2013;41(9):1671–8.

    Article  CAS  Google Scholar 

  51. Hansard MJ, et al. A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Behav Pharmacol. 2011;22(3):269–74.

    Article  CAS  Google Scholar 

  52. Kielbasa W, Kalvass JC, Stratford R. Microdialysis evaluation of atomoxetine brain penetration and central nervous system pharmacokinetics in rats. Drug Metab Dispos. 2009;37(1):137–42.

    Article  CAS  Google Scholar 

  53. Kielbasa W, Stratford RE. Exploratory translational modeling approach in drug development to predict human brain pharmacokinetics and pharmacologically relevant clinical doses. Drug Metab Dispos. 2012;40(5):877–83.

    Article  CAS  Google Scholar 

  54. Masters AR, et al. Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatogr B. 2016;1015–1016:201–8

  55. Dunner DL, Billow AA, et al. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry. 1998;59:366–73.

    Article  CAS  Google Scholar 

  56. Stahl SM, et al. A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor. Prim Care Compan J Clin Psychiatry. 2004;6(4):159–66.

    Article  Google Scholar 

  57. Connarn JN, et al. Metabolism of bupropion by carbonyl reductases in liver and intestine. Drug Metab Dispos. 2015;43(7):1019–27.

    Article  CAS  Google Scholar 

  58. Bruijnzeel AW, Markou A. Characterization of the effects of bupropion on the reinforcing properties of nicotine and food in rats. Synapse. 2003;50(1):20–8.

    Article  CAS  Google Scholar 

  59. Dalgaard L. Comparison of minipig, dog, monkey and human drug metabolism and disposition. J Pharmacol Toxicol Methods. 2015;74:80–92.

    Article  CAS  Google Scholar 

  60. Wang X, et al. Metabolism of bupropion by baboon hepatic and placental microsomes. Biochem Pharmacol. 2011;82(3):295–303.

    Article  CAS  Google Scholar 

  61. Schindler CW, et al. Comparison of the effects of methamphetamine, bupropion and methylphenidate on the self-administration of methamphetamine by rhesus monkeys. Exp Clin Psychopharmacol. 2011;19(1):1–10.

    Article  CAS  Google Scholar 

  62. Banks ML, Smith DA, Blough BE. Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys. Behav Pharmacol. 2016;27(2–3 Spec Iss):196–203.

  63. Miksys S, et al. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology. 2003;45(1):122–32.

    Article  CAS  Google Scholar 

  64. Avdeef A. Permeability: blood-brain barrier in absorption and drug development solubility, permeability, and charge state. Hoboken: Wiley; 2012. p. 595.

    Book  Google Scholar 

Download references

Acknowledgements

The authors thank Brandon Gufford (Indiana University), Jennifer Sager (Gilead Sciences), Andrea Masters (Indiana University), and Zeruesenay Desta (Indiana University) and Sara Quinney (Indiana University) for their technical advice.

Author information

Author notes

  1. Chandrali Bhattacharya

    Present address: Department of Pharmacy Practice, Purdue University, Indianapolis, IN, 46202, USA

  2. Robert E. Stratford

    Present address: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA, 15282, USA

    Chandrali Bhattacharya & Robert E. Stratford

  2. Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA, 15282, USA

    Danielle Kirby & Michael Van Stipdonk

  3. Indiana University School of Medicine, Research II, Suite 480, 950 W. Walnut St, Indianapolis, IN, 46202-5188, USA

    Robert E. Stratford

Authors
  1. Chandrali Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danielle Kirby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Van Stipdonk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert E. Stratford
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Participated in research design: CB, DK, RES, MVS. Conducted experiments: CB and DK. Performed data analysis: CB and DK. Wrote or contributed to the writing of the manuscript: CB, DK, RES, MVS.

Corresponding author

Correspondence to Robert E. Stratford.

Ethics declarations

Funding

The studies reported in this publication were supported by a grant from the Charles Henry Leach II fund.

Conflict of interest

All the authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 306 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhattacharya, C., Kirby, D., Van Stipdonk, M. et al. Comparison of In Vitro Stereoselective Metabolism of Bupropion in Human, Monkey, Rat, and Mouse Liver Microsomes. Eur J Drug Metab Pharmacokinet 44, 261–274 (2019). https://doi.org/10.1007/s13318-018-0516-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-018-0516-4

Search

Navigation