View source for Hydroxybupropion

{{Short description|Group of stereoisomers}}
{{Drugbox
| IUPAC_name = (±)-1-(3-Chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone
| image = Hydroxybupropion.svg
| width = 225px

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 357399-43-0
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = V94F513635
| ATC_prefix = None
| ATC_suffix = 
| PubChem = 446
| DrugBank = 
| ChemSpiderID = 433
| ChEBI = 166487
| ChEMBL = 3544616
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 15–25 hours
| excretion = 
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category= 
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = 
| routes_of_administration = 
| synonyms = BW 306U; 6-Hydroxybupropion

<!--Chemical data-->
| C=13 | H=18 | Cl=1 | N=1 | O=2
| SMILES = O=C(c1cc(Cl)ccc1)C(NC(C)(C)CO)C
| StdInChI = 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
| StdInChIKey = AKOAEVOSDHIVFX-UHFFFAOYSA-N
}}

'''Hydroxybupropion''' (code name '''BW 306U'''), or '''6-hydroxybupropion''', is the major [[active metabolite]] of the [[antidepressant]] and [[smoking cessation]] drug [[bupropion]].<ref name="Dwoskin_2014">{{cite book | vauthors = Dwoskin LP | title = Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse | url = https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA177 | date = 29 January 2014 | publisher = Elsevier Science | isbn = 978-0-12-420177-4 | pages = 177–216 | access-date = 25 October 2016 | archive-date = 4 June 2020 | archive-url = https://web.archive.org/web/20200604173051/https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA177 | url-status = live }}</ref> It is formed from bupropion by the [[liver]] [[enzyme]] [[CYP2B6]] during [[first-pass metabolism]].<ref name="Dwoskin_2014" /> With oral bupropion treatment, hydroxybupropion is present in [[blood plasma|plasma]] at [[area under the curve (pharmacokinetics)|area under the curve]] concentrations that are as many as 16–20 times greater than those of bupropion itself,<ref name="Dwoskin_2014" /><ref name="Lemke_2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA612|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=612–|access-date=25 October 2016|archive-date=11 December 2021|archive-url=https://web.archive.org/web/20211211192841/https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA612|url-status=live}}</ref> demonstrating extensive conversion of bupropion into hydroxybupropion in humans.<ref name="Dwoskin_2014" /> 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.<ref name="Dwoskin_2014" /> Other metabolites of bupropion besides hydroxybupropion include [[threohydrobupropion]] and [[erythrohydrobupropion]].<ref name="Costa_2019">{{cite journal | vauthors = Costa R, Oliveira NG, Dinis-Oliveira RJ | title = Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects | journal = Drug Metabolism Reviews | volume = 51 | issue = 3 | pages = 293–313 | date = August 2019 | pmid = 31124380 | doi = 10.1080/03602532.2019.1620763 | s2cid = 163167323 }}</ref><ref name="Jefferson_2005" />

==Pharmacology==
{| class="wikitable plainrowheaders" style="float:right; clear:right; margin:1em auto 1em 1em;"
|+Pharmacology of bupropion and its metabolites.
|- style="text-align:center;"
!scope="col"|&nbsp;
!scope="col"| Bupropion
!scope="col"| ''R,R''-<br />Hydroxy<br />bupropion
!scope="col"| ''S,S''-<br />Hydroxy<br />bupropion
!scope="col"| ''Threo''-<br />hydro<br />bupropion
!scope="col"| ''Erythro''-<br />hydro<br />bupropion
|- style="text-align:center;"
!scope="row" colspan="6" | Exposure and half-life
|- style="text-align:center;"
!scope="row"| [[Area under the curve (pharmacokinetics)|AUC]] relative<br />to bupropion<ref name="Kharasch_2019">{{cite journal | vauthors = Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Schweiger J, Miller JP, Lenze EJ | display-authors = 6 | title = Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial | journal = Clinical Pharmacology and Therapeutics | volume = 105 | issue = 5 | pages = 1164–1174 | date = May 2019 | pmid = 30460996 | pmc = 6465131 | doi = 10.1002/cpt.1309 }}</ref><ref name="Kharasch_2020">{{cite journal | vauthors = Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ | title = Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults | journal = Clinical Pharmacology and Therapeutics | volume = 108 | issue = 5 | pages = 1036–1048 | date = November 2020 | pmid = 32386065 | doi = 10.1002/cpt.1888 | s2cid = 218563059 }}</ref>
| 1
| 23.8
| 0.6
| 11.2
| 2.5
|- style="text-align:center;"
!scope="row"| Half-life<ref name="Masters_2016">{{cite journal | vauthors = Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z | title = Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 358 | issue = 2 | pages = 230–238 | date = August 2016 | pmid = 27255113 | pmc = 4959100 | doi = 10.1124/jpet.116.232876 }}</ref>
| 11&nbsp;h
| 19&nbsp;h
| 15&nbsp;h
| 31&nbsp;h
| 22&nbsp;h
|- style="text-align:center;"
!scope="row" colspan="6" | Inhibition [[IC50|IC<sub>50</sub>]] (μM) in human cells, unless noted otherwise
|- style="text-align:center;"
!scope="row"| [[Dopamine transporter|DAT]], uptake<ref name="Lukas_2010">{{cite journal | vauthors = Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI | display-authors = 6 | title = Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 12 | pages = 4731–4748 | date = June 2010 | pmid = 20509659 | pmc = 2895766 | doi = 10.1021/jm1003232 }}</ref>
| 0.66
| inactive
| 0.63
| 47 (rat)<ref name="Sánchez_1999">{{cite journal | vauthors = Sánchez C, Hyttel J | title = Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 4 | pages = 467–489 | date = August 1999 | pmid = 10379421 | doi = 10.1023/a:1006986824213 | s2cid = 19490821 }}</ref>
| no data
|- style="text-align:center;"
!scope="row"| [[Norepinephrine transporter|NET]], uptake<ref name="Lukas_2010"/>
| 1.85
| 9.9
| 0.24
| 16 (rat)<ref name="Sánchez_1999"/>
| no data
|- style="text-align:center;"
!scope="row"| [[Serotonin transporter|SERT]], uptake<ref name="Lukas_2010"/>
| inactive
| inactive
| inactive
| 67 (rat)<ref name="Sánchez_1999"/>
| no data
|- style="text-align:center;"
!scope="row"| [[alpha-3 beta-4 nicotinic receptor|α{{sub|3}}β{{sub|4}}]] nicotinic<ref name="Lukas_2010"/>
| 1.8
| 6.5
| 11
| 14 (rat)<ref name="Bondarev_2003">{{cite journal | vauthors = Bondarev ML, Bondareva TS, Young R, Glennon RA | title = Behavioral and biochemical investigations of bupropion metabolites | journal = European Journal of Pharmacology | volume = 474 | issue = 1 | pages = 85–93 | date = August 2003 | pmid = 12909199 | doi = 10.1016/S0014-2999(03)02010-7 }}</ref>
| no data
|- style="text-align:center;"
!scope="row"| [[Alpha-4 beta-2 nicotinic receptor|α{{sub|4}}β{{sub|2}}]] nicotinic<ref name="Damaj_2004"/>
| 12
| 31
| 3.3
| no data
| no data
|- style="text-align:center;"
!scope="row"| [[CHRNA1|α{{sub|1}}β{{sub|1}}γδ]] nicotinic<ref name="Damaj_2004"/>
| 7.9
| 7.6
| 28
| no data
| no data
|- style="text-align:center;"
|}

===Pharmacodynamics===
Compared to bupropion, hydroxybupropion is similar in its [[potency (pharmacology)|potency]] as a [[norepinephrine reuptake inhibitor]] ([[IC50|IC<sub>50</sub>]] = 1.7 μM), but is substantially weaker as a [[dopamine reuptake inhibitor]] (IC<sub>50</sub> = >10 μM).<ref name="Damaj_2004">{{cite journal | vauthors = Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR | display-authors = 6 | title = Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors | journal = Molecular Pharmacology | volume = 66 | issue = 3 | pages = 675–682 | date = September 2004 | pmid = 15322260 | doi = 10.1124/mol.104.001313 | s2cid = 1577336 }}</ref> Like bupropion, hydroxybupropion is also a [[non-competitive antagonist]] of [[nicotinic acetylcholine receptor|nACh receptor]]s, such as [[alpha-4 beta-2 nicotinic receptor|α<sub>4</sub>β<sub>2</sub>]] and [[alpha-3 beta-4 nicotinic receptor|α<sub>3</sub>β<sub>4</sub>]], but is even more potent in comparison.<ref name="Dwoskin_2014" /><ref name="Damaj_2004" /><ref name="Zhu_2012">{{cite journal | vauthors = Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, Benowitz NL, Tyndale RF | display-authors = 6 | title = CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion | journal = Clinical Pharmacology and Therapeutics | volume = 92 | issue = 6 | pages = 771–777 | date = December 2012 | pmid = 23149928 | pmc = 3729209 | doi = 10.1038/clpt.2012.186 }}</ref><ref name="Foxhall_2014">{{cite book| vauthors = Foxhall LE, Rodriguez MA |title=Advances in Cancer Survivorship Management|url=https://books.google.com/books?id=YIjLBAAAQBAJ&pg=PA265|date=11 October 2014|publisher=Springer|isbn=978-1-4939-0986-5|pages=265–|access-date=25 October 2016|archive-date=20 March 2017|archive-url=https://web.archive.org/web/20170320130715/https://books.google.com/books?id=YIjLBAAAQBAJ&pg=PA265|url-status=live}}</ref><ref name="Johnson_2010">{{cite book| vauthors = Johnson BA |title=Addiction Medicine: Science and Practice|url=https://books.google.com/books?id=zvbr4Zn9S9MC&pg=PA433|date=10 October 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-0338-9|pages=433–|access-date=25 October 2016|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427000558/https://books.google.com/books?id=zvbr4Zn9S9MC&pg=PA433|url-status=live}}</ref>

===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 80-90%.<ref name= "Dhillon">{{cite journal | vauthors = Dhillon S, Yang LP, Curran MP | title = Bupropion: a review of its use in the management of major depressive disorder | journal = Drugs | volume = 68 | issue = 5 | pages = 653–689 | year = 2008 | pmid = 18370448 | doi = 10.2165/00003495-200868050-00011 }}</ref><ref name="PubChem_62889">{{cite web | work = PubChem | publisher = National Center for Biotechnology Information. | title = Buproprion, CID 62889 | url = https://pubchem.ncbi.nlm.nih.gov/compound/62884?from=summary }}</ref> Its distribution half-life is between 3–4 hours and exhibits moderate human plasma protein binding (between 82–88%) with the parent compound and hydroxybupropion displaying the highest affinity.<ref name="Glaxosmithkline2004">{{cite web | work = Glaxosmithkline | date = 2004 | title = Bupropion hydrochloride Tablets | url = https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-20-tab11A-Wellbutrin-Tabs-SLR028.pdf | archive-url = https://web.archive.org/web/20170516184618/https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-20-tab11A-Wellbutrin-Tabs-SLR028.pdf | archive-date=2017-05-16 }}</ref><ref name="Jefferson_2005">{{cite journal | vauthors = Jefferson JW, Pradko JF, Muir KT | title = Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations | journal = Clinical Therapeutics | volume = 27 | issue = 11 | pages = 1685–1695 | date = November 2005 | pmid = 16368442 | doi = 10.1016/j.clinthera.2005.11.011 }}</ref> 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.<ref name="Glaxosmithkline2004" /> C<sub>max</sub> vales 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.<ref name="Glaxosmithkline2004" /><ref name="Jefferson_2005" />

==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, hydroxybuproprion 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.<ref>{{cite web | title = Orangebook, Lists of: Scheduling Actions Controlled Substances Regulated Chemicals | work = Drug and Chemical Evaluation Section Office of Diversion Control Drug Enforcement Administration | publisher = U.S. Department of Justice | url = http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | archive-url = https://web.archive.org/web/20160417085648/http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | archive-date=2016-04-17 }}</ref> One can access GLP (Good Lab Practice) documents detailing assays/techniques to further research and isolate this drug.<ref name="Walsky_2004">{{cite journal | vauthors = Walsky RL, Obach RS | title = Validated assays for human cytochrome P450 activities | journal = Drug Metabolism and Disposition | volume = 32 | issue = 6 | pages = 647–660 | date = June 2004 | pmid = 15155557 | doi = 10.1124/dmd.32.6.647 | s2cid = 8789343 }}</ref><ref>{{cite journal | vauthors = Coles R, Kharasch ED | title = Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 857 | issue = 1 | pages = 67–75 | date = September 2007 | pmid = 17656162 | doi = 10.1016/j.jchromb.2007.07.007 }}</ref> 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.<ref>{{cite journal | vauthors = Hamad MO, Kiptoo PK, Stinchcomb AL, Crooks PA | title = Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6beta-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents | journal = Bioorganic & Medicinal Chemistry | volume = 14 | issue = 20 | pages = 7051–7061 | date = October 2006 | pmid = 16798000 | doi = 10.1016/j.bmc.2006.06.018 }}</ref>

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.<ref>{{cite book | doi=10.1016/B978-0-12-420118-7.00005-6 | chapter=Bupropion and Bupropion Analogs as Treatments for CNS Disorders | series=Advances in Pharmacology | pages=177–216 | pmid=24484978 | volume=69 | year=2014 |vauthors=Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI | title=Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse | isbn=9780124201187 }}</ref><ref name="Zhu_2012" /> 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.<ref>{{cite journal | vauthors = Kiptoo PK, Paudel KS, Hammell DC, Pinninti RR, Chen J, Crooks PA, Stinchcomb AL | title = Transdermal delivery of bupropion and its active metabolite, hydroxybupropion: a prodrug strategy as an alternative approach | journal = Journal of Pharmaceutical Sciences | volume = 98 | issue = 2 | pages = 583–594 | date = February 2009 | pmid = 18623203 | pmc = 2612091 | doi = 10.1002/jps.21463 }}</ref> 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 ==
{{Reflist}}

{{Monoamine reuptake inhibitors}}
{{Nicotinic acetylcholine receptor modulators}}
{{Phenethylamines}}

[[Category:5-HT3 antagonists]]
[[Category:Antidepressants]]
[[Category:Cathinones]]
[[Category:Chloroarenes]]
[[Category:Convulsants]]
[[Category:Human drug metabolites]]
[[Category:Nicotinic antagonists]]
[[Category:Norepinephrine reuptake inhibitors]]
[[Category:Primary alcohols]]
[[Category:Smoking cessation]]
[[Category:Stimulants]]