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Other names | BW 306U; 6-Hydroxybupropion |
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Pharmacokinetic data | |
Elimination half-life | 15–25 hours |
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Chemical and physical data | |
Formula | C13H18ClNO2 |
Molar mass | 255.74 g·mol−1 |
3D model (JSmol) | |
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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]
Bupropion | R,R- Hydroxy bupropion | S,S- Hydroxy bupropion | Threo- hydro bupropion | Erythro- hydro bupropion | |
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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 |
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]
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]
Hydroxybupropion is a racemic mixture of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion.
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.
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(2R,3R)-Hydroxybupropion, or simply (R,R)-hydroxybupropion, is the major metabolite of the antidepressant, smoking cessation, and appetite suppressant medication bupropion. It is the (2R,3R)-enantiomer of hydroxybupropion, which in humans occurs as a mixture of (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion (radafaxine). Hydroxybupropion is formed from bupropion mainly by the cytochrome P450 enzyme CYP2B6. Levels of (2R,3R)-hydroxybupropion are dramatically higher than those of bupropion and its other metabolites during bupropion therapy.
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.
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].
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).