Mechanism of Action
The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of serotonin.
Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied.
Following chronic dosing of Aplenzin 348 mg Tablets, the mean peak steady-state plasma concentration and area under the curve of bupropion were 134.3 (± 38.2) ng/mL and 1409 (± 346) ngâˆ™hr/mL, respectively. Steady-state plasma concentrations of bupropion were reached within 8 days. The elimination half-life (±SD) of bupropion after a single dose is 21.3 (± 6.7) hours.
In a study comparing 10-day dosing with Aplenzin Tablets 348 mg once daily and WELLBUTRIN XL Tablets 300 mg once daily, following a 3-day titration with once daily WELLBUTRIN XL® Tablets 150 mg, Aplenzin peak plasma concentration and area under the curve for bupropion and the 3 metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion) were equivalent to WELLBUTRIN XL Tablets 300 mg, with the average being 8-14% lower.
In a single dose study, two Aplenzin Tablets 174 mg once daily and one Aplenzin Tablet 348 mg once daily were evaluated. Equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the 3 metabolites.
Additionally, a multiple dose study compared 14-day dosing with Aplenzin Tablets 522 mg once daily to dosing with three Aplenzin Tablets 174 mg once daily, following a 3-day titration with one Aplenzin Tablet 174 mg once daily, and a succeeding 5-day titration with two Aplenzin tablets 174 mg once daily. Equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the 3 metabolites.
These findings demonstrate that Aplenzin Tablets 174 mg, 348 mg and 522 mg are dose proportional. A 348 mg dose can be achieved by administering either one Aplenzin Tablet 348 mg or two Aplenzin Tablets 174 mg. A 522 mg dose can be achieved by administering either one Aplenzin Tablet 522 mg, three Aplenzin Tablets 174 mg, or one Aplenzin Tablet 174 mg plus one Aplenzin Tablet 348 mg.
Following single oral administration of Aplenzin Tablets 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 and time to peak plasma concentration of bupropion; area under the curve was increased by 19%.
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.
Bupropion is extensively metabolized in humans. Three metabolites have been shown to be 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 cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion. 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 or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme [see
DRUG INTERACTIONS: Drugs Metabolized by Cytochrome P450IID6 (CYP2D6)
Following chronic administration in healthy volunteers, peak plasma concentration of hydroxybupropion occurred approximately 6 hours after administration of Aplenzin tablets. The peak plasma concentrations of hydroxybupropion were approximately 9 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 24.3 (± 4.9) hours, and its AUC at steady state is about 15.6 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion. However, the elimination half-lives of erythrohydrobupropion and threohydrobupropion are longer, approximately 31.1(± 7.8) and 50.8 (± 8.5) hours, respectively, and steady-state AUCs were 1.5 and 6.8 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day of bupropion hydrochloride (equivalent to 348 mg and 522 mg of bupropion hydrobromide, respectively).
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.
Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.
The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in patients with mild to severe cirrhosis. The first study showed that the half-life of hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in 8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers [see
DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Hepatic Function, WARNINGS AND PRECAUTIONS: Hepatic Impairment
USE IN SPECIFIC POPULATIONS: Hepatic Impairment
There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with endstage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. The elimination of the major metabolites of bupropion may be reduced by impaired renal function [see
DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Renal Function and USE IN SPECIFIC POPULATIONS: Renal Impairment
Left Ventricular Dysfunction
During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy volunteers.
The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see
USE IN SPECIFIC POPULATIONS: Geriatric Use
Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared to female volunteers. The clinical significance of this finding is unknown.
The effects of cigarette smoking on the pharmacokinetics of bupropion hydrochloride were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day bupropion hydrochloride, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day of bupropion hydrochloride (approximately 2 to 7 times the MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in one Ames bacterial mutagenicity assay, but was negative in another. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.