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
liverenzymeCYP2B6 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]
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
^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.
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abcSánchez 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.
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10.1023/a:1006986824213.
PMID10379421.
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^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.
PMID12909199.
^
abcdDamaj 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.
PMID15322260.
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^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.
PMID15155557.
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^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.
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^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.
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^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.
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