Bupropion hydrochloride ((±) α-t-butylamino-3-chloropropiophenone HCl): a novel antidepressant agent

Soroko, Francis E.; Mehta, Nariman B.; Maxwell, Robert A.; Ferris, Robert M.; Schroeder, David H.

doi:10.1111/j.2042-7158.1977.tb11460.x

Cited by 119 publications

(49 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acute and chronically administered BUP has repeatedly been demonstrated to dose dependently increase locomotor activity in rodents with similar potency, regardless of species, age, or strain (Soroko et al, 1977;Nielsen et al, 1986;Zarrindast and Hosseini-Nia, 1988;Vassout et al, 1993;Redolat et al, 2005;Mitchell et al, 2006;Billes and Cowley, 2007). The current finding that BUP, DA, and DA + NE reuptake inhibition all transiently increased locomotor activity is consistent with the idea that inhibition of the DA transporter is sufficient to cause a significant short-term increase in locomotion and even reverse the decrease in activity caused by inhibition of NE reuptake.…”

Section: Discussionsupporting

confidence: 77%

“…Because reports on the acute effects of BUP on temperature are inconsistent, further research is needed to determine if increased thermogenesis might also contribute to increased energy expenditure by BUP (Zarrindast and Abolfathi-Araghi, 1992;Liu et al, 2002;Hasegawa et al, 2005). We and others have shown that acute peripheral BUP also dose dependently stimulates locomotor activity in rodents, an effect that is consistent with inhibition of the DA transporter (Soroko et al, 1977;Cooper et al, 1980;Nielsen et al, 1986;Zarrindast and Hosseini-Nia, 1988;Vassout et al, 1993;Redolat et al, 2005;Mitchell et al, 2006).…”

Section: Introductionmentioning

confidence: 71%

See 1 more Smart Citation

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA + NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA + NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA + NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA + NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA + NE reuptake (with GBR + NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 71%

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Billes

Cowley

2007

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Alterations in the metabolism of bupropion and its primary metabolites have been posited to contribute to this variability. Early animal studies suggest that bupropion is a more effective antidepressant in mice than in rats (Soroko et al, 1977;Ferris et al, 1983), and hydroxybupropion plasma exposure was much higher in mice than in rats (Welch et al, 1987). Thus, differences in the formation of potentially active metabolites may explain species differences in bupropion effect.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Gufford

Metzger

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Bupropion is a widely used antidepressant and smoking cessation aid in addition to being one of two US Food and Drug Administration-recommended probe substrates for evaluation of cytochrome P450 2B6 activity. Racemic bupropion undergoes oxidative and reductive metabolism, producing a complex profile of pharmacologically active metabolites with relatively little known about the mechanisms underlying their elimination. A liquid chromatography-tandem mass spectrometry assay was developed to simultaneously separate and detect glucuronide metabolites of (R,R)-and (S,S)-hydroxybupropion, (R,R)-and (S,S)-hydrobupropion (threo) and (S,R)-and (R,S)-hydrobupropion (erythro), in human urine and liver subcellular fractions to begin exploring mechanisms underlying enantioselective metabolism and elimination of bupropion metabolites. Human liver microsomal data revealed marked glucuronidation stereoselectivity [Cl int , 11.4 versus 4.3 ml/min per milligram for the formation of (R,R)-and (S,S)-hydroxybupropion glucuronide; and Cl max , 7.7 versus 1.1 ml/min per milligram for the formation of (R,R)-and (S,S)-hydrobupropion glucuronide], in concurrence with observed enantioselective urinary elimination of bupropion glucuronide conjugates. Approximately 10% of the administered bupropion dose was recovered in the urine as metabolites with glucuronide metabolites, accounting for approximately 40%, 15%, and 7% of the total excreted hydroxybupropion, erythrohydrobupropion, and threo-hydrobupropion, respectively. Elimination pathways were further characterized using an expressed UDP-glucuronosyl transferase (UGT) panel with bupropion enantiomers (both individual and racemic) as substrates. UGT2B7 catalyzed the stereoselective formation of glucuronides of hydroxybupropion, (S,S)-hydrobupropion, (S,R)-and (R,S)-hydrobupropion; UGT1A9 catalyzed the formation of (R,R)-hydrobupropion glucuronide. These data systematically describe the metabolic pathways underlying bupropion metabolite disposition and significantly expand our knowledge of potential contributors to the interindividual and intraindividual variability in therapeutic and toxic effects of bupropion in humans.

show abstract

“…The first evidence linking BUP metabolism to effect was observed when BUP was shown to be more effective in mouse models of depression than in rat models of depression (Soroko et al, 1977;Ferris et al, 1983). This species difference was later explained by the ability of mice to convert BUP to 4-hydroxybupropion (OHBUP) (active metabolite), whereas rats cleared BUP through alternate detoxification pathways (Suckow et al, 1986;Welch et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Masters

Gufford

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug-drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n 5 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography-tandem mass spectrometry assays. Time-dependent, elimination rate-limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and C max ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S-versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steadystate pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300-312 hours) from 185 to 37,447 nM×h] and elimination [terminal half-life of approximately 7-46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion's effects and DDIs with CYP2D6.

show abstract

Bupropion hydrochloride ((±) α-t-butylamino-3-chloropropiophenone HCl): a novel antidepressant agent

Cited by 119 publications

References 9 publications

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis

Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Contact Info

Product

Resources

About