Clinical Pharmacology
Pharmacodynamics and Pharmacological Actions:
The neurochemical mechanism of the antidepressant effect of bupropion is not known. Bupropion does not inhibit monoamine oxidase. Compared to classical tricyclic antidepressants, it is a weak blocker of the neuronal uptake of serotonin and norepinephrine;
it also inhibits the neuronal re-uptake of dopamine to some extent.
Bupropion produces dose-related CNS stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped
behavior.
Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose recommended as the human antidepressant dose.
Absorption, Distribution, Pharmacokinetics, Metabolism, and Elimination:
Oral bioavailability and single-dose pharmacokinetics:
In humans, following oral administration of bupropion, peak plasma bupropion concentrations are usually achieved within 2 hours, followed by a biphasic decline. The average half-life of the second (post-distributional) phase is approximately
14 hours, with a range of 8 to 24 hours. Six hours after a single dose, plasma bupropion concentrations are approximately 30% of peak concentrations. Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250
mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use.
The absolute bioavailability of bupropion tablets in humans has not been determined because an intravenous formulation for human use is not available.
However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. For example, the absolute bioavailability of bupropion in animals (rats and dogs) ranges from 5% to 20%.
Metabolism:
Following oral administration of 200 mg of 14C-bupropion, 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 documenting the extensive metabolism of bupropion.
Several of the known metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion have not been fully characterized. However, because of their longer elimination half-lives, the plasma concentrations
of at least two of the known metabolites can be expected, especially in chronic use, to be very much higher than the plasma concentration of bupropion. This is of potential clinical importance because 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 extend of accumulation of these active metabolites.
Furthermore, bupropion has been shown to induce its own metabolism in three animal species (mice, rats, and dogs) following subchronic administration. If induction also occurs in humans, the relative contribution of bupropion and its metabolites
to the clinical effects of bupropion may be changed in chronic use.
Plasma and urinary metabolites so far identified include biotransformation products formed via reduction of the carbonyl group and/or hydroxylation of the tert-butyl group of bupropion. Four basic metabolites have been identified.
They are the erythro- and threo-amino alcohols of bupropion, the erythro-amino diol of bupropion, and a morpholinol, metabolite (formed from hydroxylation of the tert-butyl group of bupropion).
The morpholinol metabolite appears in the systemic circulation almost as rapidly as the parent drug following a single oral dose. Its peak level is three times the peak level of the parent drug; it has a half life on the order of 24 hours;
and its AUC 0 to 60 hours is about 15 times that of bupropion.
The threo-amino alcohol metabolite has a plasma concentration time profile similar to that of the morpholinol metabolite. The erythro-amino alcohol and the erythro-amino diol metabolites generally cannot be detected in
the systemic circulation following a single oral dose of the parent drug. The morpholinol and the threo-amino alcohol metabolites have been found to be half as potent as bupropion in animal screening tests for antidepressant drugs.
During a chronic dosing study in 14 depressed patients with left ventricular dysfunction, it was found that there was substantial interpatient variability (two- to five-fold) in the trough steady-state concentrations of bupropion and the morpholinol
and threo-amino alcohol metabolites. In addition, the steady-state plasma concentrations of these metabolites were 10 to 100 times the steady-state concentrations of the parent drug.
The effect of other disease states and altered organ function on the metabolism and/or elimination of bupropion has not been studied in detail. However, 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 conjugation in the liver prior to urinary excretion. The preliminary results of a comparative single-dose pharmacokinetic study in normal versus cirrhotic
patients indicated that half-lives of the metabolites were prolonged by cirrhosis and that the metabolites accumulated to levels two to three times those in normals.
The effect of age on plasma concentrations of bupropion and its metabolites has not been characterized.
In vitro tests show that bupropion is 80% or more bound to human albumin at plasma concentrations up to 800 micromolar (200 mcg/mL).
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