Clinical data | |
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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 |
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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 16–20 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 | 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 [5] [6] | 1 | 23.8 | 0.6 | 11.2 | 2.5 |
Half-life [7] | 11 h | 19 h | 15 h | 31 h | 22 h |
Inhibition IC50 (μM) in human cells, unless noted otherwise | |||||
DAT, uptake [8] | 0.66 | inactive | 0.63 | 47 (rat) [9] | no data |
NET, uptake [8] | 1.85 | 9.9 | 0.24 | 16 (rat) [9] | no data |
SERT, uptake [8] | inactive | inactive | inactive | 67 (rat) [9] | no data |
α3β4 nicotinic [8] | 1.8 | 6.5 | 11 | 14 (rat) [10] | no data |
α4β2 nicotinic [11] | 12 | 31 | 3.3 | no data | no data |
α1β1γδ nicotinic [11] | 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). [11] 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] [11] [12] [13] [14]
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]
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. [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.
Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants. Sertraline is effective for panic disorder, social anxiety disorder, generalized anxiety disorder (GAD), and obsessive–compulsive disorder (OCD). However, for OCD, cognitive behavioral therapy, particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder (PTSD), sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder (PMDD) and can be used in sub-therapeutic doses or intermittently for its treatment.
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Bupropion, sold under the brand name Wellbutrin among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cases of "incomplete response" to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue. Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder.
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Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
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Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
Lobeline is a piperidine alkaloid found in a variety of plants, particularly those in the genus Lobelia, including Indian tobacco, Devil's tobacco, great lobelia, Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder which is freely soluble in water.
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