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Pharmacology Page 2
Elimination: In 2 single-dose (150 mg) studies the mean (±% CV) apparent clearance (Cl/F) of bupropion was 135 (±20%) and 209 L/hr (±21%). Following chronic dosing of 150 mg of Wellbutrin SR
every 12 hours for 14 days (n=34), the mean Cl/F at steady state was 160 L/h (±23%). The mean elimination half-life of bupropion (estimated from a series of studies) is approximately 21 hours. Estimates of the half-lives of the metabolites
determined from a multiple-dose study were 20 hours (±25%) for hydroxybupropion, 37 hours (±35%) for threohydrobupropion, and 33 hours (±30%) for erythrohydrobupropion. Steady-state plasma concentrations of bupropion and metabolites
are reached within 5 and 8 days, respectively. Following oral administration of 200 mg of 4-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral dose of bupropion
excreted unchanged was only 0.5%. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 150 to 300 mg/day.
Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure, 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 disposition of buproprion following a single 200 mg oral dose was compared in 8 healthy volunteers and 8 weight- and age-matched volunteers with alcoholic liver disease. The half-life of hydroxybuproprion was significantly prolonged in subjects
with alcoholic liver disease (32 hours versus 21 hours). The differences in half-life for bupropion and the other metabolites in the two patients groups were minimal.
In patients with renal or hepatic impairment, treatment should be initiated at reduced dosage (see Precautions and Dosage).
In a single dose study, there were no significant differences in the pharmacokinetics of bupropion or its major metabolites in smokers compared with nonsmokers.
The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized (see Precautions and Dosage).
Metabolism: Bupropion is extensively metabolized in humans. There are 3
active metabolites: hydroxybupropion and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via hydroxylation of the tert-butyl group of bupropion and/or reduction of the carbonyl group. 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. In preclinical tests used to predict antidepressant activity, it has been observed that hydroxybupropion
is comparable in potency to bupropion, while the other metabolites are one half to one tenth as potent. This may be of clinical importance because the plasma concentrations of the metabolites are higher than those of bupropion.
In vitro results indicate that biotransformation of bupropion to hydroxybupropion is catalyzed primarily by CYP2B6, and to a much lesser extent by CYP1A2, 2A6, 2C9, 2E1 and 3A4 isozymes. Detectable levels of hydroxybupropion are not observed with
CYP1A1 and CYP2D6 isozymes. Cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion. Following a single 150 mg dose of bupropion in humans, peak plasma concentrations of hydroxybupropion occur approximately 6 hours
after administration. Peak plasma concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state. The AUC of hydroxybupropion at steady state is about 17-fold higher than that of bupropion. The
times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. |
