Amfebutamone, also known as bupropion, inhibits CYP2D6 with an IC50 of 58 μM[1]. Atypical antidepressants like bupropion cause endoplasmic reticulum stress and cytotoxicity in SH-SY5Y cells that is dependent on caspase [3]. By triggering the endoplasmic reticulum stress response and JNK activation, bupropion activates caspase 3, which causes apoptosis in SH-SY5Y cells [3]. 1–100 µg/mL of bupropion decreases cell viability. The apoptotic pathway may be the cause of the bupropion-induced reduction in cell viability [3]. Within an hour, bupropion (100 μg/mL) enhances the expression of phosphorylated versions of JNK, p38 MAPK, EIF-2α, and GRP78 [3].

In mice, amfebutamone exhibits both convulsant and anticonvulsant properties. Bupropion causes dose-dependent clonic convulsions in mice, with a convulsant dosage 50 (or CD50) of 119.7 mg/kg, which is the level at which 50% of mice have convulsions [4]. In male albino mice weighing 22–30 g, bupropion (10, 15, 20, and 40 mg/kg, i.p.) dose-dependently decreased immobility time in comparison to vehicle controls (in seconds). Bupropion was observed to decrease the immobility phase in the forced swim test and tail suspension test, with ED50 values of 18.5 and 18 mg/kg ip, respectively. Bupropion (10, 20, and 40 mg/kg, intraperitoneally) raises the concentration of homovanillic acid, a metabolite of free dopamine, in the mouse brain in a dose-dependent manner [5].

Cell Viability Assay [3]
Cell Types: SH-SY5Y human catecholaminergic cells
Tested Concentrations: 0, 1, 10, 50 and 100 µg/mL
Incubation Duration: 24 hrs (hours)
Experimental Results: Cell viability diminished Dramatically in a concentration-dependent manner.

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Western Blot Analysis [3]
Cell Types: SH-SY5Y human catecholaminergic cells
Tested Concentrations: 100 μg/mL
Incubation Duration: 1, 3, 8, 24 hrs (hours)
Experimental Results: Immunity to p-EIF-2α within 1 hour of bupropion treatment Reactivity increased Dramatically and persisted for 3 hrs (hours), indicating that bupropion rapidly stimulates PERK. The expression of GRP78 was slightly but Dramatically increased and JNK was Dramatically activated. Early activation of ER stress pathways by bupropion returned to basal levels 8 hrs (hours) after treatment.

Animal/Disease Models: Male Swiss mouse, weight 20-25 grams [4]
Doses: 100-160 mg/kg
Route of Administration: IP
Experimental Results:Caused clonic convulsions, CD50 and CD97 were 119.7 (104.1-137.6) and 156.7 respectively mg/kg. When administered at the full convulsive dose of 160 mg/kg, the median latency was 6.00 minutes (3.50-8.15). Catalonic convulsions were only observed occasionally (1 in 8 mice) in groups receiving doses of 140 or 160 mg/kg.

Absorption, Distribution and Excretion
Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). **Immediate Release Formulation** In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. **Sustained Release Formulation** In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. **Extended Release Formulation** Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.
Peak plasma bupropion concentrations usually occur within 2 or 3 hours after oral administration of the conventional or extended-release, film-coated tablets (Wellbutrin SR, Zyban), respectively, to healthy individuals. Plasma bupropion concentrations following administration of single oral doses of 100-250 mg and with chronic administration of up to 450 mg daily are proportional to dose. Steady-state plasma concentrations of bupropion are achieved within 8 days. During chronic administration of bupropion hydrochloride as conventional or extended-release, film-coated tablets at a dosage of 100 mg 3 times daily or 150 mg twice daily, respectively, peak plasma concentrations of the drug at steady state with extended-release tablets were about 85% of measurements for the conventional tablets. Equivalence in area under the plasma concentration-time curve (AUC) of bupropion was shown for the formulations, which demonstrated that at steady state the conventional and extended-release tablets are essentially bioequivalent. The drug exhibits linear pharmacokinetics during chronic administration of bupropion hydrochloride dosages of 300-450 mg daily.
Bupropion hydrochloride appears to be well absorbed from the GI tract following oral administration. The oral bioavailability of bupropion in humans has not been elucidated because a preparation for IV administration is not available. However, the relative proportion of an oral dose reaching systemic circulation unchanged appears likely to be small. In animals, the oral bioavailability of bupropion varies from 5-20%. Food does not appear to affect substantially the peak plasma concentration or area under the plasma concentration-time curve of bupropion achieved with extended-release tablets of the drug; these measures reportedly were increased with food by 11 or 17%, respectively.
Approximately 87 and 10% of an orally administered, radiolabeled dose of bupropion are excreted in urine and feces, respectively. Unchanged drug comprised 0.5% of the dose excreted.
Plasma concentrations of bupropion decline in a biphasic manner.1 57 61 130 A decline to approximately 30% of the peak plasma bupropion concentration is observed 6 hours after administration of a single oral dose of the drug.
For more Absorption, Distribution and Excretion (Complete) data for Bupropion (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.
Bupropion appears to be metabolized extensively, probably in the liver. The 3 active metabolites that have been identified are formed through reduction of the carbonyl group and/or hydroxylation. The basic metabolites identified include the erythro- and threo-amino alcohols of bupropion, and a morpholinol metabolite. The amino-alcohol isomers threohydrobupropion and erythrohydrobupropion are formed by reduction of the carbonyl group of bupropion, and the morpholinol metabolite, hydroxybupropion, is formed by hydroxylation of the tert-butyl group of bupropion. The metabolites of bupropion exhibit linear pharmacokinetics during chronic administration of the drug at dosages of 300-450 mg daily.
All available antidepressants with the exception of fluvoxamine and nefazodone either are metabolized by cytochrome P450 2D6 (CYP2D6) and/or inhibit this isozyme. To date, nothing in this regard has been published concerning bupropion. We report that plasma level/dose ratios for bupropion, and its metabolites erythrohydrobupropion and threohydrobupropion, were not associated with debrisoquine metabolic status in 12 patients, three of whom were poor 2D6 metabolizers. The plasma level/dose ratios for the metabolite hydroxybupropion were, however, significantly higher in poor 2D6 metabolizers. In three patients, who received a second phenotyping test during treatment with bupropion, debrisoquine metabolic ratios were not increased. It is thus inferred that bupropion is neither metabolized by nor inhibits CYP2D6. The potential accumulation of hydroxybupropion after CYP2D6 inhibition may, however, contribute to toxicity and impair bupropion's therapeutic effectiveness
Bupropion hydrochloride is a new monocyclic antidepressant. In humans, its disposition results in the formation of three major metabolites: the morpholinol metabolite, the erythroamino alcohol, and the threoamino alcohol metabolite. Bupropion's disposition was monitored following a single oral 200 mg dose in eight healthy volunteers and eight age- (44.5 +/- 8.4 years) and weight- (77.4 +/- 6.7 kg) matched volunteers with alcoholic liver disease. This latter group is of interest because the incidence of depression is more frequent in alcoholics than in the general population, and the liver is the major route of elimination for cyclic antidepressants. The mean elimination half-life of the morpholinol metabolite was significantly prolonged in subjects with alcoholic liver disease (32.2 +/- 13.5 vs. 21.1 +/- 4.9 hours (p less than 0.05), while the differences in bupropion (17.3 +/- 8.6 hours vs. 16.5 +/- 10.4 hours for healthy subjects and subjects with alcoholic liver disease, respectively), erythroamino alcohol (26.1 +/- 13.3 hours vs. 29.8 +/- 6.9 hours for healthy subjects and subjects with alcoholic liver disease, respectively), and threoamino alcohol (25.5 +/- 8.6 hours vs. 23.4 +/- 10.7 hours for healthy subjects and subjects with alcoholic liver disease, respectively) were minimal. Mean area under the plasma concentration time curves for bupropion and metabolites were increased in subjects with alcoholic liver disease; however, clear differences between means of these small groups did not emerge, probably due to the increased variability of bupropion pharmacokinetics in these subjects. As a therapeutic agent for the treatment of depression in chronic alcoholics who may consume alcohol in combination with their antidepressant therapy, the lack of sedation with bupropion could be advantageous.
We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients. The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations. Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of treatment with bupropion.
For more Metabolism/Metabolites (Complete) data for Bupropion (9 total), please visit the HSDB record page.
Reduction of the carbonyl groupand/or hydroxylation of the tert-butyl group of bupropion.
Route of Elimination: Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.
Half Life: 24 hours

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Biological Half-Life
24 hours
The half-life of bupropion in the terminal phase averages about 14 hours (range: 8-24 hours) following single doses; with multiple dosing, the half-life of bupropion in the terminal phase reportedly averages 21 hours (range: 8-39 hours). In a limited number of geriatric patients with a major depressive episode, the half-life of bupropion in the terminal phase averaged about 34 hours after a single oral dose of the drug.

Toxicity Summary
IDENTIFICATION AND USE: Bupropion is pale yellow oil formulated in extended release oral tablets. Bupropion is a dopamine uptake inhibitor, which is used as a second generation antidepressive agent. HUMAN EXPOSURE AND TOXICITY: Bupropion is an antidepressant commonly prescribed as a smoking cessation aid. It has effects on dopamine and norepinephrine, and can lower seizure threshold, particularly in overdose. Several cases of recreational use of bupropion via nasal insufflation have been reported in the literature. One of the potentially most serious adverse effects of bupropion is reduction in the seizure threshold. However, despite the potential seriousness of this effect, seizures remain a relatively uncommon adverse effect of bupropion therapy. Patients reportedly have overdosed with 30 g or more of bupropion hydrochloride. Serious effects of overdosage have included seizures in about one-third of such patients, hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Lethargy, grogginess, tremors, jitteriness, confusion, lightheadedness, paresthesias, visual hallucinations, blurred vision, nausea, and vomiting also have occurred. Overdosage of bupropion (mainly as part of multiple drug overdoses) reportedly has resulted in fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Recovery without sequelae has been reported in most individuals following an overdose of bupropion alone. However, massive overdosage of bupropion alone has been reported rarely to result in death preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest. Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion. Unintentional ingestion of bupropion in young children has generally resulted in limited toxicity. In two deaths attributed to bupropion, the doses in both cases were estimated to be less than 10 g. ANIMAL STUDIES: In lifetime carcinogenicity studies of rats or mice receiving bupropion hydrochloride dosages of 100-300 or 150 mg/kg daily respectively, an increase in nodular proliferative lesions of the liver was observed in rats but not in mice. The relationship of these lesions to the development of neoplasms of the liver is unclear. An increase in malignant tumors of the liver and other organs was not observed in either rats or mice. A fertility study in rats using oral bupropion hydrochloride dosages of up to 300 mg/kg daily did not reveal evidence of impaired fertility. In rats receiving oral dosages of bupropion of up to 300 mg/kg daily prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. In developmental studies performed in rats and rabbits, no clear evidence of teratogenic activity was found in either species, but slightly increased incidences of fetal malformations and skeletal variations were observed in rabbits. Bupropion induced behavioral changes in rats and mice. Bupropion exhibited mutagenic activity in the Salmonella microbial mutagen (Ames) test system; the mutation rate was 2-3 times control in 2 of 5 strains. An increase in chromosomal aberrations was observed in one of 3 in vivo cytogenetic studies conducted with the bone marrow of rats.
Bupropion selectively inhibits the neuronal reuptake of dopamine, norepinephrine, and serotonin; actions on dopaminergic systems are more significant than imipramine or amitriptyline whereas the blockade of norepinephrine and serotonin reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. The increase in norepinephrine may attenuate nicotine withdrawal symptoms and the increase in dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Bupropion exhibits moderate anticholinergic effects.

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Interactions
Adverse neuropsychiatric events or reduced alcohol tolerance have been reported rarely in patients who ingested alcohol during bupropion therapy. Because of concerns that excessive use of alcohol or abrupt withdrawal from alcohol may be associated with an increased risk of seizures during bupropion therapy, patients receiving the drug should be advised to minimize or, if possible, avoid alcohol consumption.
Concomitant administration of bupropion and carbamazepine resulted in decreases in the peak plasma concentration of bupropion and in the 24-hour area under the plasma concentration-time curve (AUC) by 87 and 90%, respectively; the peak plasma concentration and 24-hour AUC of the metabolite, hydroxybupropion, were increased by 71 and 50%, respectively.138 In contrast, concomitant administration of bupropion and valproate sodium resulted only in an increase by 94% in 24-hour AUC of hydroxybupropion.138
A limited number of patients with parkinsonian syndrome treated with either amantadine or levodopa appeared to have a high incidence of adverse effects (e.g., nausea and vomiting, excitement and restlessness, postural tremor) when bupropion was used concurrently. Caution should be exercised if bupropion therapy is initiated in a patient receiving levodopa or amantadine, including use of low initial dosage and increasing the dosage gradually in small increments.
Evidence from animal studies suggests that concomitant administration of bupropion and monoamine oxidase (MAO) inhibitors is potentially hazardous. In animals, phenelzine enhanced the acute toxicity of bupropion, as indicated by an increase in mortality and a decrease in time to death. The manufacturer states that concurrent administration of bupropion and MAO inhibitors is contraindicated and that at least 2 weeks elapse following discontinuance of an MAO inhibitor prior to initiation of bupropion therapy
For more Interactions (Complete) data for Bupropion (20 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse ip 230 mg/kg
LD50 Mouse oral 575 mg/kg
LD50 Rat ip 210 mg/kg
LD50 Rat oral 600 mg/kg

[1]. C Lindsay DeVane. Antidepressant-drug interactions are potentially but rarely clinically significant. Neuropsychopharmacology. 2006 Aug;31(8):1594-604; discussion 1614-5.

[2]. Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine depe.

[3]. Bupropion, an atypical antidepressant, induces endoplasmic reticulum stress and caspase-dependent cytotoxicity in SH-SY5Y cells. Toxicology. 2011 Jul 11;285(1-2):1-7.

[4]. Convulsant and anticonvulsant effects of bupropion in mice. Eur J Pharmacol. 2004 Sep 19;499(1-2):117-20.

[5]. Moreira, R., The efficacy and tolerability of bupropion in the treatment of major depressive disorder. Clin Drug Investig, 2011. 31 Suppl 1: p. 5-17.

Bupropion is an aromatic ketone that is propiophenone carrying a tert-butylamino group at position 2 and a chloro substituent at position 3 on the phenyl ring. It has a role as an antidepressant, an environmental contaminant and a xenobiotic. It is a secondary amino compound, a member of monochlorobenzenes and an aromatic ketone.
Bupropion (also known as the brand name product Wellbutrin®) is a norepinephrine/dopamine-reuptake inhibitor (NDRI) used most commonly for the management of Major Depressive Disorder (MDD), Seasonal Affective Disorder (SAD), and as an aid for smoking cessation. Bupropion exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor. A Cochrane Review of meta-analyses of available treatment modalities for smoking cessation found that abstinence rates approximately doubled when bupropion was used as compared to placebo, and was found to have similar rates of smoking cessation as [nicotine] replacement therapy (NRT). Bupropion is sometimes used as an add-on agent to first-line treatments of depression such as selective serotonin reuptake inhibitor (SSRI) medications when there is a treatment-failure or only partial response. Bupropion is also used off-label for the management of Attention/Deficit-Hyperactivity Disorder (ADHD) in adults with comorbid bipolar depression to avoid mood destabilization caused by typical stimulant medications used for the treatment of ADHD. When used in combination with [naltrexone] in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and [naltrexone] increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. The combination of naltrexone and bupropion was shown to result in a statistically significant weight loss, with a mean change in body weight of -6.3% compared to -1.3% for placebo.
Bupropion is an Aminoketone. The mechanism of action of bupropion is as a Dopamine Uptake Inhibitor, and Norepinephrine Uptake Inhibitor. The physiologic effect of bupropion is by means of Increased Dopamine Activity, and Increased Norepinephrine Activity.
Bupropion is an aminoketone antidepressant that is widely used in therapy of depression and smoking cessation. Bupropion therapy can be associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.
Bupropion is an aminoketone with antidepressant activity. The molecular mechanism of the antidepressant effect of bupropion is unknown. This agent does not inhibit monoamine oxidase and, compared to classical tricyclic antidepressants, is a weak blocker of the neuronal uptake of serotonin and norepinephrine. Buproprion also weakly inhibits the neuronal re-uptake of dopamine.
Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO. The antidepressant effect of bupropion is considered to be mediated by its dopaminergic and noradrenergic action. Bupropion has also been shown to act as a competitive alpha-3-beta-4- nicotinic antagonist, the alpha-3-beta-4-antagonism has been shown to interrupt addiction in studies of other drugs such as ibogaine. This alpha-3-beta-4-antagonism correlates quite well with the observed effect of interrupting addiction. A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment; Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO. The antidepressant effect of bupropion is considered to be mediated by its dopaminergic and noradrenergic action. Bupropion has also been shown to act as a competitive alpha-3-beta-4-nicotinic antagonist, the alpha-3-beta-4-antagonism has been shown to interrupt addiction in studies of other drugs such as ibogaine. This alpha-3-beta-4-antagonism correlates quite well with the observed effect of interrupting addiction. Bupropion (amfebutamone) (brand names Wellbutrin and Zyban) is an antidepressant of the aminoketone class, chemically unrelated to tricyclics or selective serotonin reuptake inhibitors (SSRIs). It is similar in structure to the stimulant cathinone, and to phenethylamines in general. It is a chemical derivative of diethylpropion, an amphetamine-like substance used as an anorectic. Bupropion is both a dopamine reuptake inhibitor and a norepinephrine reuptake inhibitor. It is often used as a smoking cessation aid.
A propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of DOPAMINE.
See also: Bupropion Hydrochloride (has salt form); Bupropion Hydrobromide (has salt form).

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Drug Indication
Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with [naltrexone] as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers.
FDA Label

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Mechanism of Action
Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with [naltrexone] in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and [naltrexone] increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways.
Unicyclic aminoketone with noradrenergic and dopaminergic activity.
Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of norepinephrine uptake. This experiment examines monoaminergic involvement in the discriminative stimulus effects of bupropion. Rats were trained to press one lever when injected i.p. with bupropion (17.0 mg/kg), and another lever when injected with saline. In substitution tests, dose-response curves were obtained for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers fully substituted for bupropion; the exception, indatraline (LU 19-005), partially substituted (71% bupropion-appropriate responding). Serotonin and norepinephrine uptake blockers (zimelidine and nisoxetine, respectively) produced negligible or limited substitution, and the anti-muscarinic dopamine uptake blocker benztropine produced limited partial substitution. A series of dopamine D1-like and D2-like receptor agonists were also tested: only the D2-like agonist RU 24213 fully substituted; three other D2-like agonists and four D1-like agonists partially substituted (50% < drug responding < 80%). Antagonism of the discriminative effects of bupropion was obtained with a D1- and a D2-like dopamine antagonist. The results demonstrate strong similarities with those obtained using other dopamine uptake inhibitors as training drugs, and support the view that the behavioural effects of bupropion are primarily mediated by dopaminergic mechanisms.
The effects of bupropion on core body temperature of intact or reserpinized mice were studied. Intraperitoneal (IP) administration of bupropion to mice induced a dose-dependent hypothermia. The response of bupropion was decreased by the D-2 antagonist sulpiride or pimozide, but not by the D-1 antagonist SCH 23390, antimuscarinic drug atropine, alpha-adrenergic blocker phenoxybenzimine, beta-adrenergic antagonist propranolol or antiserotonergic methergoline. Reserpine induced hypothermia, which was reversed by bupropion administration. The reversal response of bupropion was reduced by propranolol, but not sulpiride, SCH 23390, phenoxybenzamine, atropine or methergoline. It is concluded that bupropion-induced hypothermia may be mediated through D-2 receptor activation, while the reversal of reserpine-induced hypothermia by bupropion may be exerted through beta-adrenergic stimulation.
Bupropion (12.5-75 mg kg-1) was given intraperitoneally to rats and was found to decrease the food consumption of the animals dose-dependently. While phenoxybenzamine, propranolol and methergoline failed to antagonize the anorectic effect of the drug; pimozide a dopamine receptor blocker decreased anorexia induced by bupropion. Bupropion (12.5-50 mg kg-1) also caused a marked increase in locomotor activity of the rats. The increase in locomotion produced by bupropion was completely antagonized by pretreatment of the animals with pimozide and reserpine plus a-methyl-p-tyrosine, but not by pretreatment with phenoxybenzamine, propranolol or methergoline. Taking into considerations the evidences of dopaminergic properties of bupropion shown by the others, it could be suggested that the anorexia and hyperactivity produced by bupropion may be induced through the indirect dopaminergic mechanism.
For more Mechanism of Action (Complete) data for Bupropion (7 total), please visit the HSDB record page.

C13H18NOCL

239.74112

239.108

34911-55-2

Bupropion hydrochloride;31677-93-7;Bupropion hydrobromide;905818-69-1

444

Pale yellow oil

1.066g/cm3

334.8ºC at 760mmHg

233-234°C

156.3ºC

3.69

1

2

4

16

247

0

CC(C(=O)C1=CC(=CC=C1)Cl)NC(C)(C)C

SNPPWIUOZRMYNY-UHFFFAOYSA-N

InChI=1S/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3

2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)