 | |
| Clinical data | |
|---|---|
| Other names | BW 306U; 6-Hydroxybupropion |
| ATC code |
|
| Pharmacokinetic data | |
| Eliminationhalf-life | 15–25 hours |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| ChemSpider | |
| UNII | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C13H18ClNO2 |
| Molar mass | 255.74 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Hydroxybupropion (code nameBW 306U), or6-hydroxybupropion, is the majoractive metabolite of theantidepressant andsmoking cessation drugbupropion.[1] It is formed from bupropion by theliverenzymeCYP2B6 duringfirst-pass metabolism.[1] With oral bupropion treatment, hydroxybupropion is present inplasma atarea 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 aprodrug to hydroxybupropion.[1]
Hydroxybupropion has twochiral centers and is amixture of four possibleenantiomers.[3][4][5] In humans, however, presumably due tosteric hindrance, only(2R,3R)-hydroxybupropion and(2S,3S)-hydroxybupropion are formed.[3][4][5]
Other metabolites of bupropion besides hydroxybupropion includethreohydrobupropion anderythrohydrobupropion.[6][7]
| 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] | 10.8 h | 19 h | 15 h | 31 h | 22 h |
| InhibitionIC50 (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 itspotency as anorepinephrine reuptake inhibitor (IC50 = 1.7 μM), but is substantially weaker as adopamine reuptake inhibitor (IC50 = >10 μM).[14] Like bupropion, hydroxybupropion is also anon-competitive antagonist ofnACh receptors, such asα4β2 andα3β4, 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 ten-fold that of bupropion. Hydroxybupropion's elimination half-life is roughly 20 hours, give or take five hours, and it reaches steady-state concentrations within eight days.[20][7]
Hydroxybupropion is aracemic 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 foralcohol 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.
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).
