Chemistry:Hydroxybupropion

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Short description: Group of stereoisomers
Hydroxybupropion
Hydroxybupropion.svg
Clinical data
Other namesBW 306U; 6-Hydroxybupropion
ATC code
  • None
Pharmacokinetic data
Elimination half-life15–25 hours
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC13H18ClNO2
Molar mass255.74 g·mol−1
3D model (JSmol)

Hydroxybupropion (code name BW 306U), or 6-hydroxybupropion, is the major active metabolite of the antidepressant and smoking cessation drug bupropion.[1] It is formed from bupropion by the liver enzyme CYP2B6 during first-pass metabolism.[1] With oral bupropion treatment, hydroxybupropion is present in plasma at area under the curve concentrations that are as many as 16–20 times greater than those of bupropion itself,[1][2] demonstrating extensive conversion of bupropion into hydroxybupropion in humans.[1] As such, hydroxybupropion is likely to play a very important role in the effects of oral bupropion, which could accurately be thought of as functioning largely as a prodrug to hydroxybupropion.[1] Other metabolites of bupropion besides hydroxybupropion include threohydrobupropion and erythrohydrobupropion.[3][4]

Pharmacology

Pharmacology of bupropion and its metabolites.
  Bupropion R,R-
Hydroxy
bupropion 		S,S-
Hydroxy
bupropion 		Threo-
hydro
bupropion 		Erythro-
hydro
bupropion
Exposure and half-life
AUC relative
to bupropion[5][6] 		1 23.8 0.6 11.2 2.5
Half-life[7] 11 h 19 h 15 h 31 h 22 h
Inhibition IC50 (μM) in human cells, unless noted otherwise
DAT, uptake[8] 0.66 inactive 0.63 47 (rat)[9] no data
NET, uptake[8] 1.85 9.9 0.24 16 (rat)[9] no data
SERT, uptake[8] inactive inactive inactive 67 (rat)[9] no data
α3β4 nicotinic[8] 1.8 6.5 11 14 (rat)[10] no data
α4β2 nicotinic[11] 12 31 3.3 no data no data
α1β1γδ nicotinic[11] 7.9 7.6 28 no data no data

Pharmacodynamics

Compared to bupropion, hydroxybupropion is similar in its potency as a norepinephrine reuptake inhibitor (IC50 = 1.7 μM), but is substantially weaker as a dopamine reuptake inhibitor (IC50 = >10 μM).[11] Like bupropion, hydroxybupropion is also a non-competitive antagonist of nACh receptors, such as α4β2 and α3β4, but is even more potent in comparison.[1][11][12][13][14]

Pharmacokinetics

Bupropion is extensively and rapidly absorbed in the gastrointestinal tract but experiences extensive first pass metabolism rendering its systemic bioavailability limited. Exact bioavailability has yet to be determined given an intravenous form does not exist. Absorption is suggested to be between 80 and 90%.[15][16] Its distribution half-life is between 3–4 hours and exhibits moderate human plasma protein binding (between 82 and 88%) with the parent compound and hydroxybupropion displaying the highest affinity.[17][4] Bupropion is a racemic mixture and is metabolized hepatically primarily via oxidative cleavage of its side chains by CYP2B6. Hydroxybupropion is the most potent of the metabolites. It is formed via the "hydroxylation of the tert-butyl group" by CYP2B6 and is excreted renally.[17] Cmax values of hydroxybupropion are 4–7 times that of bupropion, while the exposure to hydroxybupropion is "10 fold" that of bupropion. Hydroxybupropion's elimination half-life is roughly 20 hours, give or take 5 hours and will reach steady state concentrations within 8 days.[17][4]

Chemistry

Hydroxybupropion is a racemic mixture of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion.

Research

Although there are patents proposing uses and formulations of this compound, hydroxybupropion is not currently marketed as a drug in and of itself and is only available for use in non-clinical research. Hydroxybupropion is not a scheduled drug or a controlled substance.[18] One can access GLP (Good Lab Practice) documents detailing assays/techniques to further research and isolate this drug.[19][20] Otherwise, there is little regulatory data available for hydroxybupropion at this time. Moreover, there is little information to suggest hydroxybupropion has an abuse potential. However, it has been studied as a possible therapeutic for alcohol and nicotine use as a codrug.[21]

There are few clinical trials or toxicology studies assessing hydroxybupropion alone at this time. There are clinical studies which assess hydroxybupropion in conjunction with bupropion suggesting hydroxybupropion to be the primary form of the compound responsible for its clinical efficacy.[22][12] Also, transdermal delivery of bupropion and hydroxybupropion has been assessed finding bupropion to be the superior candidate given its elevated diffusion rate through skin samples.[23] There are few toxicology studies assessing hydroxybupropion alone at this time. However, there are some studies which assess this compound in conjunction with others or its parent compound.

See also

  • Radafaxine – a cyclised derivative of hydroxybupropion
  • Manifaxine – an analogue of radafaxine and hydroxybupropion

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. 29 January 2014. pp. 177–216. ISBN 978-0-12-420177-4. https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA177. Retrieved 25 October 2016. 
  2. ↑ Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 24 January 2012. pp. 612–. ISBN 978-1-60913-345-0. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA612. Retrieved 25 October 2016. 
  3. ↑ "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metabolism Reviews 51 (3): 293–313. August 2019. doi:10.1080/03602532.2019.1620763. PMID 31124380. 
  4. ↑ 4.0 4.1 4.2 "Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations". Clinical Therapeutics 27 (11): 1685–1695. November 2005. doi:10.1016/j.clinthera.2005.11.011. PMID 16368442. 
  5. ↑ "Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial". Clinical Pharmacology and Therapeutics 105 (5): 1164–1174. May 2019. doi:10.1002/cpt.1309. PMID 30460996. 
  6. ↑ "Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults". Clinical Pharmacology and Therapeutics 108 (5): 1036–1048. November 2020. doi:10.1002/cpt.1888. PMID 32386065. 
  7. ↑ "Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers". The Journal of Pharmacology and Experimental Therapeutics 358 (2): 230–238. August 2016. doi:10.1124/jpet.116.232876. PMID 27255113. 
  8. ↑ 8.0 8.1 8.2 8.3 "Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation". Journal of Medicinal Chemistry 53 (12): 4731–4748. June 2010. doi:10.1021/jm1003232. PMID 20509659. 
  9. ↑ 9.0 9.1 9.2 "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology 19 (4): 467–489. August 1999. doi:10.1023/a:1006986824213. PMID 10379421. 
  10. ↑ "Behavioral and biochemical investigations of bupropion metabolites". European Journal of Pharmacology 474 (1): 85–93. August 2003. doi:10.1016/S0014-2999(03)02010-7. PMID 12909199. 
  11. ↑ 11.0 11.1 11.2 11.3 "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors". Molecular Pharmacology 66 (3): 675–682. September 2004. doi:10.1124/mol.104.001313. PMID 15322260. 
  12. ↑ 12.0 12.1 "CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion". Clinical Pharmacology and Therapeutics 92 (6): 771–777. December 2012. doi:10.1038/clpt.2012.186. PMID 23149928. 
  13. ↑ Advances in Cancer Survivorship Management. Springer. 11 October 2014. pp. 265–. ISBN 978-1-4939-0986-5. https://books.google.com/books?id=YIjLBAAAQBAJ&pg=PA265. Retrieved 25 October 2016. 
  14. ↑ Addiction Medicine: Science and Practice. Springer Science & Business Media. 10 October 2010. pp. 433–. ISBN 978-1-4419-0338-9. https://books.google.com/books?id=zvbr4Zn9S9MC&pg=PA433. Retrieved 25 October 2016. 
  15. ↑ "Bupropion: a review of its use in the management of major depressive disorder". Drugs 68 (5): 653–689. 2008. doi:10.2165/00003495-200868050-00011. PMID 18370448. 
  16. ↑ "Bupropion, CID 62889". PubChem. National Center for Biotechnology Information.. https://pubchem.ncbi.nlm.nih.gov/compound/62884?from=summary. 
  17. ↑ 17.0 17.1 17.2 "Bupropion hydrochloride Tablets". Glaxosmithkline. 2004. https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-20-tab11A-Wellbutrin-Tabs-SLR028.pdf. 
  18. ↑ "Orangebook, Lists of: Scheduling Actions Controlled Substances Regulated Chemicals". Drug and Chemical Evaluation Section Office of Diversion Control Drug Enforcement Administration. U.S. Department of Justice. http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf. 
  19. ↑ "Validated assays for human cytochrome P450 activities". Drug Metabolism and Disposition 32 (6): 647–660. June 2004. doi:10.1124/dmd.32.6.647. PMID 15155557. 
  20. ↑ "Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 857 (1): 67–75. September 2007. doi:10.1016/j.jchromb.2007.07.007. PMID 17656162. 
  21. ↑ "Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6beta-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents". Bioorganic & Medicinal Chemistry 14 (20): 7051–7061. October 2006. doi:10.1016/j.bmc.2006.06.018. PMID 16798000. 
  22. ↑ "Bupropion and Bupropion Analogs as Treatments for CNS Disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. 69. 2014. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 9780124201187. 
  23. ↑ "Transdermal delivery of bupropion and its active metabolite, hydroxybupropion: a prodrug strategy as an alternative approach". Journal of Pharmaceutical Sciences 98 (2): 583–594. February 2009. doi:10.1002/jps.21463. PMID 18623203. 



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