Hydroxybupropion

Last updated
Hydroxybupropion
Hydroxybupropion.svg
Clinical data
Other namesBW 306U; 6-Hydroxybupropion
ATC code
  • None
Pharmacokinetic data
Elimination half-life 15–25 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
Formula C13H18ClNO2
Molar mass 255.74 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]

Contents

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

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] 		123.80.611.22.5
Half-life [10] 1.04 h19 h15 h31 h22 h
Inhibition IC50 (μM) in human cells, unless noted otherwise
DAT, uptake [11] 0.66inactive0.6347 (rat) [12] no data
NET, uptake [11] 1.859.90.2416 (rat) [12] no data
SERT, uptake [11] inactiveinactiveinactive67 (rat) [12] no data
α3β4 nicotinic [11] 1.86.51114 (rat) [13] no data
α4β2 nicotinic [14] 12313.3no datano data
α1β1γδ nicotinic [14] 7.97.628no datano 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). [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

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

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. [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

Related Research Articles

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References

  1. 1 2 3 4 5 6 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.
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  5. 1 2 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).
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  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.
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