What is the metabolism of Bupropion (Wellbutrin)?

From the Guidelines

Bupropion is primarily metabolized in the liver through multiple pathways, with the main metabolic route involving the cytochrome P450 enzyme CYP2B6, which converts bupropion to its active metabolite hydroxybupropion, as reported in the most recent study 1. The metabolism of bupropion involves several key steps and enzymes.

• The main metabolic route involves the cytochrome P450 enzyme CYP2B6, which converts bupropion to its active metabolite hydroxybupropion.
• Other important metabolites include threohydrobupropion and erythrohydrobupropion, which are formed through reduction of the ketone group by carbonyl reductase enzymes.
• These metabolites are pharmacologically active and contribute to bupropion's therapeutic effects.
• Hydroxybupropion has a longer half-life (about 20 hours) than the parent compound (about 12 hours), allowing for sustained clinical effects, as noted in 1.
• Genetic variations in CYP2B6 can affect bupropion metabolism, potentially leading to differences in drug response and side effect profiles among individuals.
• Since bupropion is metabolized by CYP2B6, medications that inhibit this enzyme (like ticlopidine or clopidogrel) may increase bupropion levels and risk of side effects.
• Conversely, CYP2B6 inducers (like carbamazepine or phenobarbital) may decrease bupropion effectiveness.
• Bupropion itself inhibits CYP2D6, potentially affecting metabolism of other medications processed by this enzyme.
• The drug and its metabolites are primarily excreted through the kidneys, with dosage adjustments recommended for patients with significant renal or hepatic impairment, as recommended in 1.

From the FDA Drug Label

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. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys.

The metabolism of Bupropion occurs in the liver, where it is converted to active metabolites, including hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. These metabolites are then further metabolized and excreted by the kidneys. The plasma concentrations of these metabolites can be as high or higher than those of bupropion, and their potency relative to bupropion is as follows:

• Hydroxybupropion: half as potent as bupropion
• Threohydrobupropion and erythrohydrobupropion: 5-fold less potent than bupropion 2

From the Research

Metabolism of Bupropion

• Bupropion undergoes metabolic transformation to an active metabolite, 4-hydroxybupropion, through hepatic cytochrome P450-2B6 (CYP2B6) 3
• The drug is extensively metabolized to form several metabolites, including oxidised hydroxybupropion and two reduced metabolites, threohydrobupropion and erythrohydrobupropion, all of which are considered to be active 4
• The enzymes that participate in the reduction of bupropion have been identified, including 11β-hydroxysteroid dehydrogenase 1, AKR1C1, AKR1C2, AKR1C3, and CBR1 4

Role of CYP2B6 in Bupropion Metabolism

• CYP2B6 is the primary enzyme responsible for the formation of hydroxybupropion, with a significant impact on bupropion exposure 5
• Genetic polymorphisms in CYP2B6 can affect the metabolism of bupropion, with CYP2B6 poor and intermediate metabolizers having significantly decreased exposures to hydroxybupropion and the active moiety 5

Other Enzymes Involved in Bupropion Metabolism

• CYP2C19 is involved in bupropion metabolism, primarily through alternate hydroxylation pathways, with higher activity at lower substrate concentrations 6
• Carbonyl reductases (CR) also play a role in the metabolism of bupropion, with 11β-dehydrogenase isozyme 1 in the liver microsome fraction and AKR7 in the intestine being responsible for the formation of threohydrobupropion 7

Metabolism of Bupropion in Different Tissues

• The liver is the primary site of bupropion metabolism, with both CYP2B6 and CR contributing to the formation of hydroxybupropion and threohydrobupropion, respectively 7
• The intestine also plays a role in the metabolism of bupropion, with CR being responsible for the formation of threohydrobupropion, although to a lesser extent than in the liver 7