Is paroxetine (Selective Serotonin Reuptake Inhibitor, SSRI) primarily metabolized by the liver or kidneys?

From the Guidelines

Paroxetine is primarily metabolized through the liver, not the kidneys. The drug undergoes extensive hepatic metabolism, mainly through the cytochrome P450 enzyme CYP2D6, which converts paroxetine into inactive metabolites 1. This liver-based metabolism means that patients with hepatic impairment may require dose adjustments, as their ability to break down the medication could be compromised, potentially leading to higher blood levels and increased side effects.

Key Points:

• Only a small amount of paroxetine is excreted unchanged in the urine, with most of the drug being eliminated as metabolites after liver processing.
• This hepatic metabolism also explains why paroxetine has potential drug interactions with other medications that use the CYP2D6 pathway.
• Patients with severe liver disease should use paroxetine with caution and may require lower doses, while kidney impairment generally doesn't significantly affect paroxetine clearance unless it's severe 1.

Clinical Implications:

• The liver's role in metabolizing paroxetine is crucial for its clearance and potential side effects.
• Monitoring and dose adjustments may be necessary in patients with liver disease to prevent adverse effects.
• The CYP2D6 enzyme's involvement in paroxetine metabolism highlights the importance of considering drug interactions when prescribing paroxetine.

From the FDA Drug Label

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. The metabolism of paroxetine is accomplished in part by CYP2D6 Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment.

Metabolism of Paroxetine: Paroxetine is extensively metabolized in the liver by the enzyme CYP2D6. The metabolites are then excreted in the urine and feces.

• Liver: The liver plays a significant role in the metabolism of paroxetine through the CYP2D6 enzyme.
• Kidneys: The kidneys are involved in the excretion of paroxetine metabolites, with approximately 64% of the dose excreted in the urine. The liver is the primary site of paroxetine metabolism, while the kidneys are involved in the excretion of the metabolites 2.

From the Research

Metabolism of Paroxetine

• Paroxetine is metabolized by the liver, specifically by the cytochrome P450 enzyme system, with CYP2D6 being one of the primary enzymes involved 3, 4, 5, 6, 7.
• The metabolism of paroxetine involves demethylenation of the methylenedioxy phenyl group, resulting in the formation of inactive metabolites 6.
• Paroxetine undergoes extensive first-pass metabolism, with less than 50% of the dose reaching the general circulation 3, 5.
• The liver plays a crucial role in the elimination of paroxetine, with approximately two-thirds of the dose being eliminated in the urine and the remainder being excreted in feces 3.

Role of CYP2D6 in Paroxetine Metabolism

• CYP2D6 is a key enzyme involved in the metabolism of paroxetine, with studies demonstrating that the enzyme is responsible for the initial step of paroxetine metabolism 6, 7.
• The activity of CYP2D6 can be inhibited by paroxetine, resulting in increased plasma levels of the drug and potentially leading to nonlinear pharmacokinetics 3, 7.
• The inhibition of CYP2D6 by paroxetine is thought to be mechanism-based, involving the formation of a metabolite intermediate complex that inactivates the enzyme 7.

Comparison with Other SSRIs

• Paroxetine is similar to other selective serotonin reuptake inhibitors (SSRIs) in terms of its metabolism, with all SSRIs undergoing extensive first-pass metabolism and being metabolized by the cytochrome P450 enzyme system 5.
• However, paroxetine is distinct from other SSRIs in terms of its potent inhibition of CYP2D6, which can lead to increased plasma levels of the drug and potentially affect the metabolism of other drugs 7.