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Hydroxybupropion

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Hydroxybupropion
Clinical data
Other namesBW 306U; 6-Hydroxybupropion
ATC code
  • None
Pharmacokinetic data
Elimination half-life15–25 hours
Identifiers
  • (±)-1-(3-Chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO2
Molar mass255.74 g·mol−1
3D model (JSmol)
  • O=C(c1cc(Cl)ccc1)C(NC(C)(C)CO)C
  • InChI=1S/C13H18ClNO2/c1-9(15-13(2,3)8-16)12(17)10-5-4-6-11(14)7-10/h4-7,9,15-16H,8H2,1-3H3
  • Key:AKOAEVOSDHIVFX-UHFFFAOYSA-N

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 to 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]

Hydroxybupropion has two chiral centers and is a mixture of four possible enantiomers.[3][4][5] In humans however, presumably due to steric hindrance, only (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion are formed.[3][4][5]

Other metabolites of bupropion besides hydroxybupropion include threohydrobupropion and erythrohydrobupropion.[6][7]

Pharmacology

[edit]
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[8][9] 		1 23.8 0.6 11.2 2.5
Half-life[10] 11 h 19 h 15 h 31 h 22 h
Inhibition IC50 (μM) in human cells, unless noted otherwise
DAT, uptake[11] 0.66 inactive 0.63 47 (rat)[12] no data
NET, uptake[11] 1.85 9.9 0.24 16 (rat)[12] no data
SERT, uptake[11] inactive inactive inactive 67 (rat)[12] no data
α3β4 nicotinic[11] 1.8 6.5 11 14 (rat)[13] no data
α4β2 nicotinic[14] 12 31 3.3 no data no data
α1β1γδ nicotinic[14] 7.9 7.6 28 no data no data

Pharmacodynamics

[edit]

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).[14] 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][14][15][16][17]

Pharmacokinetics

[edit]

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%.[18][19] 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.[20][7] 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.[20] 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.[20][7]

Chemistry

[edit]

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

Research

[edit]

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.[21] One can access GLP (Good Lab Practice) documents detailing assays/techniques to further research and isolate this drug.[22][23] 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.[24]

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.[25][15] 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.[26] 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

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

References

[edit]
  1. ^ a b c d e f Dwoskin LP (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 177–216. ISBN 978-0-12-420177-4. Archived from the original on 4 June 2020. Retrieved 25 October 2016.
  2. ^ Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 612–. ISBN 978-1-60913-345-0. Archived from the original on 11 December 2021. Retrieved 25 October 2016.
  3. ^ a b Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Adv Pharmacol. 69: 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. PMID 24484978. The hydroxylation of bupropion to form hydroxybupropion occurs by cytochrome P450 2B6 (CYP2B6) oxidation (Faucette et al., 2000; Faucette, Hawke, Shord, Lecluyse, & Lindley, 2001; Hesse et al., 2000), and the subsequent cyclization results in the creation of a second chiral center with the potential for the generation of two diastereomers (Suckow, Zhang, & Cooper, 1997). Interestingly, only the trans-diastereomers, (2S,3S)- and (2R,3R)-hydroxybupropion (2a and 2b, respectively), have been found in plasma in humans and when synthesized de novo (Fang et al., 2000), indicating that they are the thermodynamically more stable isomers. Steric hindrance greatly reduces cyclization to the cis-diastereomers, (2R,3S)- and (2S,3R)-hydroxybupropion (Suckow et al., 1997). The chirality of the second stereocenters is determined by the configuration of the existing stereocenter alpha to the ketone derived from either (S)- or (R)- bupropion.
  4. ^ a b Niemegeers P, Dumont GJ, Patteet L, Neels H, Sabbe BG (September 2013). "Bupropion for the treatment of seasonal affective disorder". Expert Opin Drug Metab Toxicol. 9 (9): 1229–1240. doi:10.1517/17425255.2013.804062. PMID 23705752. As hydroxybupropion has two chiral centers, there are four possible enantiomers. However, only (R,R)-hydroxybupropion and (S,S)-hydroxybupropion are found in human plasma [62].
  5. ^ a b Eap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C (October 2021). "Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants". World J Biol Psychiatry. 22 (8): 561–628. doi:10.1080/15622975.2021.1878427. hdl:11250/2981927. PMID 33977870. Bupropion is chiral and CYP2B6 stereoselective metabolism is observed with (S)-bupropion being metabolised at more than three times the rate of (R)-bupropion (Coles and Kharasch 2008). Because hydroxybupropion has two chiral centres, four enantiomers should be observed: however, only (R,R)-hydroxybupropion and (S,S)- hydroxybupropion are found (Coles and Kharasch 2008).
  6. ^ Costa R, Oliveira NG, Dinis-Oliveira RJ (August 2019). "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metabolism Reviews. 51 (3): 293–313. doi:10.1080/03602532.2019.1620763. PMID 31124380. S2CID 163167323.
  7. ^ a b c Jefferson JW, Pradko JF, Muir KT (November 2005). "Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations". Clinical Therapeutics. 27 (11): 1685–1695. doi:10.1016/j.clinthera.2005.11.011. PMID 16368442.
  8. ^ Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Schweiger J, et al. (May 2019). "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. doi:10.1002/cpt.1309. PMC 6465131. PMID 30460996.
  9. ^ Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ (November 2020). "Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults". Clinical Pharmacology and Therapeutics. 108 (5): 1036–1048. doi:10.1002/cpt.1888. PMID 32386065. S2CID 218563059.
  10. ^ Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z (August 2016). "Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers". The Journal of Pharmacology and Experimental Therapeutics. 358 (2): 230–238. doi:10.1124/jpet.116.232876. PMC 4959100. PMID 27255113.
  11. ^ a b c d Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, et al. (June 2010). "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. doi:10.1021/jm1003232. PMC 2895766. PMID 20509659.
  12. ^ a b c Sánchez C, Hyttel J (August 1999). "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. doi:10.1023/a:1006986824213. PMID 10379421. S2CID 19490821.
  13. ^ Bondarev ML, Bondareva TS, Young R, Glennon RA (August 2003). "Behavioral and biochemical investigations of bupropion metabolites". European Journal of Pharmacology. 474 (1): 85–93. doi:10.1016/S0014-2999(03)02010-7. PMID 12909199.
  14. ^ a b c d Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, et al. (September 2004). "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors". Molecular Pharmacology. 66 (3): 675–682. doi:10.1124/mol.104.001313. PMID 15322260. S2CID 1577336.
  15. ^ a b Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, et al. (December 2012). "CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion". Clinical Pharmacology and Therapeutics. 92 (6): 771–777. doi:10.1038/clpt.2012.186. PMC 3729209. PMID 23149928.
  16. ^ Foxhall LE, Rodriguez MA (11 October 2014). Advances in Cancer Survivorship Management. Springer. pp. 265–. ISBN 978-1-4939-0986-5. Archived from the original on 20 March 2017. Retrieved 25 October 2016.
  17. ^ Johnson BA (10 October 2010). Addiction Medicine: Science and Practice. Springer Science & Business Media. pp. 433–. ISBN 978-1-4419-0338-9. Archived from the original on 27 April 2021. Retrieved 25 October 2016.
  18. ^ Dhillon S, Yang LP, Curran MP (2008). "Bupropion: a review of its use in the management of major depressive disorder". Drugs. 68 (5): 653–689. doi:10.2165/00003495-200868050-00011. PMID 18370448. S2CID 195687060.
  19. ^ "Bupropion, CID 62889". PubChem. National Center for Biotechnology Information.
  20. ^ a b c "Bupropion hydrochloride Tablets" (PDF). Glaxosmithkline. 2004. Archived from the original (PDF) on 2017-05-16.
  21. ^ "Orangebook, Lists of: Scheduling Actions Controlled Substances Regulated Chemicals" (PDF). Drug and Chemical Evaluation Section Office of Diversion Control Drug Enforcement Administration. U.S. Department of Justice. Archived from the original (PDF) on 2016-04-17.
  22. ^ Walsky RL, Obach RS (June 2004). "Validated assays for human cytochrome P450 activities". Drug Metabolism and Disposition. 32 (6): 647–660. doi:10.1124/dmd.32.6.647. PMID 15155557. S2CID 8789343.
  23. ^ Coles R, Kharasch ED (September 2007). "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. doi:10.1016/j.jchromb.2007.07.007. PMID 17656162.
  24. ^ Hamad MO, Kiptoo PK, Stinchcomb AL, Crooks PA (October 2006). "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. doi:10.1016/j.bmc.2006.06.018. PMID 16798000.
  25. ^ Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and Bupropion Analogs as Treatments for CNS Disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 9780124201187. PMID 24484978.
  26. ^ Kiptoo PK, Paudel KS, Hammell DC, Pinninti RR, Chen J, Crooks PA, Stinchcomb AL (February 2009). "Transdermal delivery of bupropion and its active metabolite, hydroxybupropion: a prodrug strategy as an alternative approach". Journal of Pharmaceutical Sciences. 98 (2): 583–594. doi:10.1002/jps.21463. PMC 2612091. PMID 18623203.
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