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

  • Chandrali Bhattacharya
  • Danielle Kirby
  • Michael Van Stipdonk
  • Robert E. StratfordEmail author
Original Research Article

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.

Notes

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 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.

Compliance with Ethical Standards

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.

Supplementary material

13318_2018_516_MOESM1_ESM.pdf (306 kb)
Supplementary material 1 (PDF 306 kb)

References

  1. 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.Google Scholar
  2. 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.Google Scholar
  3. 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.Google Scholar
  4. 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.Google Scholar
  5. 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.Google Scholar
  6. 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.Google Scholar
  7. 7.
    Woodcock J, Khan M, Yu LX. Withdrawal of generic budeprion for nonbioequivalence. N Engl J Med. 2012;367(26):2463–5.Google Scholar
  8. 8.
    Golden RN, et al. Bupropion in depression. II. The role of metabolites in clinical outcome. Arch Gen Psychiatry. 1988;45(2):145–9.Google Scholar
  9. 9.
    Connarn JN, et al. Identification of non-reported bupropion metabolites in human plasma. Biopharm Drug Dispos. 2016;37(9):550–60.Google Scholar
  10. 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.Google Scholar
  11. 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.Google Scholar
  12. 12.
    Zhu AZX, et al. CYP2B6 and bupropion’s smoking-cessation pharmacology: the role of hydroxybupropion. Clin Pharmacol Ther. 2012;92(6):771–7.Google Scholar
  13. 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.Google Scholar
  14. 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.Google Scholar
  15. 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.Google Scholar
  16. 16.
    Grandas F, López-Manzanares L. Bupropion-induced parkinsonism. Mov Disord. 2007;22(12):1830–1.Google Scholar
  17. 17.
    Davidson J. Seizures and bupropion: a review. J Clin Psychopharmacol. 1990;10(1):60–2.Google Scholar
  18. 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.Google Scholar
  19. 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.Google Scholar
  20. 20.
    Gufford BT, et al. Stereoselective glucuronidation of bupropion metabolites in vitro and in vivo. Drug Metab Dispos. 2016;44(4):544–53.Google Scholar
  21. 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.Google Scholar
  22. 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.Google Scholar
  23. 23.
    Coles R, Kharasch ED. Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomes. Pharm Res. 2008;25(6):1405–11.Google Scholar
  24. 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.Google Scholar
  25. 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.Google Scholar
  26. 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.Google Scholar
  27. 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.Google Scholar
  28. 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.Google Scholar
  29. 29.
    Silverstone PH, et al. Convulsive liability of bupropion hydrochloride metabolites in Swiss albino mice. Ann Gen Psychiatry. 2008;7:19.Google Scholar
  30. 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.Google Scholar
  31. 31.
    Swan GE, et al. Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics J. 2004;5:21.Google Scholar
  32. 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.Google Scholar
  33. 33.
    Bondarev ML, et al. Behavioral and biochemical investigations of bupropion metabolites. Eur J Pharmacol. 2003;474(1):85–93.Google Scholar
  34. 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.Google Scholar
  35. 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.Google Scholar
  36. 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.Google Scholar
  37. 37.
    Ascher JA, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395–401.Google Scholar
  38. 38.
    Schroeder DH. Metabolism and kinetics of bupropion. J Clin Psychiatry. 1983;44(5 Pt 2):79–81.Google Scholar
  39. 39.
    Martin P, et al. Antidepressant profile of bupropion and three metabolites in mice. Pharmacopsychiatry. 1990;23(04):187–94.Google Scholar
  40. 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.Google Scholar
  41. 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.Google Scholar
  42. 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.Google Scholar
  43. 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.Google Scholar
  44. 44.
    Ferguson CS, Tyndale RF. Cytochromes P450 in the brain: emerging evidence for biological significance. Trends Pharmacol Sci. 2011;32(12):708–14.Google Scholar
  45. 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.Google Scholar
  46. 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.Google Scholar
  47. 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.Google Scholar
  48. 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.Google Scholar
  49. 49.
    Welch RM, Lai AA, Schroeder DH. Pharmacological significance of the species differences in bupropion metabolism. Xenobiotica. 1987;17(3):287–98.Google Scholar
  50. 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.Google Scholar
  51. 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.Google Scholar
  52. 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.Google Scholar
  53. 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.Google Scholar
  54. 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;1015–1016:201–8Google Scholar
  55. 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.Google Scholar
  56. 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.Google Scholar
  57. 57.
    Connarn JN, et al. Metabolism of bupropion by carbonyl reductases in liver and intestine. Drug Metab Dispos. 2015;43(7):1019–27.Google Scholar
  58. 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.Google Scholar
  59. 59.
    Dalgaard L. Comparison of minipig, dog, monkey and human drug metabolism and disposition. J Pharmacol Toxicol Methods. 2015;74:80–92.Google Scholar
  60. 60.
    Wang X, et al. Metabolism of bupropion by baboon hepatic and placental microsomes. Biochem Pharmacol. 2011;82(3):295–303.Google Scholar
  61. 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.Google Scholar
  62. 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.Google Scholar
  63. 63.
    Miksys S, et al. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology. 2003;45(1):122–32.Google Scholar
  64. 64.
    Avdeef A. Permeability: blood-brain barrier in absorption and drug development solubility, permeability, and charge state. Hoboken: Wiley; 2012. p. 595.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Chandrali Bhattacharya
    • 1
    • 4
  • Danielle Kirby
    • 2
  • Michael Van Stipdonk
    • 2
  • Robert E. Stratford
    • 1
    • 3
    • 5
    Email author
  1. 1.Graduate School of Pharmaceutical SciencesDuquesne UniversityPittsburghUSA
  2. 2.Department of Chemistry and BiochemistryDuquesne UniversityPittsburghUSA
  3. 3.Indiana University School of MedicineIndianapolisUSA
  4. 4.Department of Pharmacy PracticePurdue UniversityIndianapolisUSA
  5. 5.Division of Clinical Pharmacology, Department of MedicineIndiana University School of MedicineIndianapolisUSA

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