Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines (noradrenaline and dopamine) with minimal effect on the re-uptake of indolamines (serotonin) and does not inhibit either monoamine oxidase. The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown.
However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
After oral administration of 150 mg bupropion hydrochloride as a prolonged release tablet to healthy volunteers, maximum plasma concentrations (Cmax) of approximately 100 nanograms per ml are observed after about 2.5 to 3 hours. The AUC and Cmax values of bupropion and its active metabolites hydroxybupropion and threohydrobupropion increase dose proportionally over a dose range of 50-200 mg following single dosing and over a dose range of 300-450 mg/day following chronic dosing. The Cmax and AUC values of hydroxybupropion are approximately 3 and 14 times higher, respectively, than bupropion Cmax and AUC values. The Cmax of threohydrobupropion is comparable with the Cmax of bupropion, while the AUC of threohydrobupropion is approximately 5 times higher than that of bupropion. Peak plasma levels of hydroxybupropion and threohydrobupropion are reached after about 6 hours following administration of a single dose of bupropion. Plasma levels of erythrohydrobupropion (an isomer of threohydrobupropion, which is also active) are not quantifiable after single dosing with bupropion.
After chronic dosing with bupropion 150 mg bid, the Cmax of bupropion is similar to values reported after single dosing. For hydroxybupropion and threohydrobupropion, the Cmax values are higher (about 4 and 7 times respectively) at steady-state than after a single dosing. Plasma levels of erythrohydrobupropion are comparable to steady-state plasma levels of bupropion. Steady-state of bupropion and its metabolites is reached within 5-8 days. The absolute bioavailability of bupropion is not known; excretion data in urine, however, show that at least 87% of the dose of bupropion is absorbed.
Two studies with bupropion SR 150mg tablets in healthy volunteers suggest that exposure to bupropion may be increased when bupropion tablets are taken with food. When taken following a high fat breakfast, peak plasma concentration of bupropion (Cmax) increased by 11% and 35% in the two studies, while the overall exposure to bupropion (AUC) increased by 16% and 19%.
Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 L.
Bupropion, hydroxybupropion and threohydrobupropion bind moderately to plasma proteins (84%, 77% and 42%, respectively). Bupropion and its active metabolites are excreted in human breast milk. Animal studies show that bupropion and its active metabolites pass the blood-brain barrier and the placenta.
Bupropion is extensively metabolised in humans. Three pharmacologically active metabolites have been identified in plasma: hydroxybupropion and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion. These may have clinical importance, as their plasma concentrations are as high or higher than those of bupropion. The active metabolites are further metabolised to inactive metabolites (some of which have not been fully characterised but may include conjugates) and excreted in the urine.
In vitro studies indicate that bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the CYP2B6, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. In contrast, formation of threohydrobupropion involves carbonyl reduction but does not involve cytochrome P450 isoenzymes.
The inhibition potential of threohydrobupropion and erythrohydrobupropion towards cytochrome P450 has not been studied.
Bupropion and hydroxybupropion are both inhibitors of the CYP2D6 isoenzyme with Ki values of 21 and 13.3μM, respectively.
Following oral administration of a single 150-mg dose of bupropion, there was no difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its major metabolites between smokers and non-smokers.
Bupropion has been shown to induce its own metabolism in animals following sub-chronic administration. In humans, there is no evidence of enzyme induction of bupropion or hydroxybupropion in volunteers or patients receiving recommended doses of bupropion hydrochloride for 10 to 45 days.
Following oral administration of 200mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. Less than 10% of this 14C dose was accounted for in the urine as active metabolites.
The mean apparent clearance following oral administration of bupropion hydrochloride is approximately 200 L/hr and the mean elimination half-life of bupropion is approximately 20 hours.
The elimination half-life of hydroxybupropion is approximately 20 hours. The elimination half-lives for threohydrobupropion and erythrohydrobupropion are longer (37 and 33 hours, respectively).
The elimination of bupropion and its active major metabolites may be reduced in patients with impaired renal function. Limited data in patients with end-stage renal failure or moderate to severely impaired renal function indicate that exposure to bupropion and/or its metabolites was increased.
The pharmacokinetics of bupropion and its active metabolites were not statistically significantly different in patients with mild to moderate cirrhosis when compared to healthy volunteers, although more variability was observed between individual patients. For patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference approximately 70% and 3-fold, respectively) and more variable when compared to the values in healthy volunteers; the mean half-life was also longer (by approximately 40%). For hydroxybupropion, the mean Cmax was lower (by approximately 70%), the mean AUC tended to be higher (by approximately 30%), the median Tmax was later (by approximately 20 hrs), and the mean half-lives were longer (by approximately 4-fold) than in healthy volunteers. For threohydrobupropion and erythrohydrobupropion, the mean Cmax tended to be lower (by approximately 30%), the mean AUC tended to be higher (by approximately 50%), the median Tmax was later (by approximately 20 hrs), and the mean half-life was longer (by approximately 2-fold) than in healthy volunteers.
Pharmacokinetic studies in the elderly have shown variable results. A single dose study showed that the pharmacokinetics of bupropion and its metabolites in the elderly do not differ from those in the younger adults. Another pharmacokinetic study, single and multiple dose, has suggested that accumulation of bupropion and its metabolites may occur to a greater extent in the elderly. Clinical experience has not identified differences in tolerability between older and younger patients, but greater sensitivity in older patients cannot be ruled out.
Reproduction toxicity studies conducted in rats at exposures similar to those obtained at the maximum recommended human dose (based on systemic data on exposure) revealed no adverse effects on fertility, pregnancy and foetal development. Reproduction toxicity studies conducted in rabbits treated with doses up to 7 times the maximum recommended human dose based on a mg/m² basis (no systemic data on exposures are available) only revealed a slight increase in skeletal variations (increased incidence of common anatomical variation of an accessory thoracic rib and delayed ossification of phalanges). Moreover at maternally toxic doses, a decrease of rabbits foetal weight was reported.
In animal experiments bupropion doses several times higher than therapeutic doses in humans caused, amongst others, the following dose-related symptoms: ataxia and convulsions in rats, general weakness, trembling and emesis in dogs and increased lethality in both species. Due to enzyme induction in animals but not in humans, systemic exposures in animals were similar to the systemic exposures seen in humans at the maximum recommended dose.
Liver changes are seen in animal studies but these reflect the action of a hepatic enzyme inducer. At recommended doses in humans, bupropion does not induce its own metabolism. This suggests that the hepatic findings in laboratory animals have only limited importance in the evaluation and risk assessment of bupropion.
Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mammalian mutagen, and therefore is of no concern as a human genotoxic agent. Mouse and rat studies confirm the absence of carcinogenicity in these species.