Hydroxybupropion
Group of stereoisomers
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Hydroxybupropion has two chiral centers and is a mixture of four possible enantiomers. In humans, however, presumably due to steric hindrance, only (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion are formed.
Other metabolites of bupropion besides hydroxybupropion include threohydrobupropion and erythrohydrobupropion.
Pharmacology
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). Like bupropion, hydroxybupropion is also a non-competitive antagonist of nACh receptors, such as α4β2 and α3β4, but is even more potent in comparison.
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%. 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. 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. 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.
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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. One can access GLP (Good Lab Practice) documents detailing assays/techniques to further research and isolate this drug. 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.
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. 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. 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.