How is Paroxetine metabolized in the liver?

From the Guidelines

Paroxetine is primarily metabolized in the liver by cytochrome P450 2D6 (CYP2D6).

Metabolism Details

• The metabolism of paroxetine is subject to genetic variation and inhibition, which can affect its plasma levels and efficacy 1.
• Studies have shown that CYP2D6 ultrarapid metabolizers have lower paroxetine plasma levels, while poor metabolizers have higher levels 1.
• The CYP2D6 genotype can influence the metabolism of paroxetine, with intermediate metabolizers having substantially elevated plasma concentrations 1.
• The metabolism of paroxetine can also be affected by other factors, such as coadministration of CYP2D6 inhibitors, which can lead to higher plasma levels and increased risk of adverse effects 1.

Clinical Implications

• Genetic testing for CYP2D6 polymorphisms may be useful in guiding treatment selection and dosing for patients taking paroxetine 1.
• Clinicians should be aware of the potential for increased plasma levels and adverse effects in patients with certain CYP2D6 genotypes or those taking concomitant CYP2D6 inhibitors 1.
• Higher dosing requirements for paroxetine in certain conditions, such as obsessive-compulsive disorder, may increase the risk of toxic blood levels and adverse effects 1.

From the FDA Drug Label

Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces The metabolism of paroxetine is accomplished in part by CYP2D6 Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment.

Paroxetine is metabolized in the liver, in part, by the CYP2D6 enzyme. The metabolites are considered to be inactive. The saturation of this enzyme at clinical doses can lead to nonlinear pharmacokinetics. 2

From the Research

Metabolism of Paroxetine in the Liver

• Paroxetine undergoes extensive first-pass metabolism in the liver, which reduces its bioavailability to about 30-60% 3, 4.
• The drug is primarily metabolized by the cytochrome P4502D6 isoenzyme, and to a lesser extent by other isoenzymes such as CYP1A2, CYP2C19, CYP3A4, and CYP3A5 4, 5.
• The metabolism of paroxetine involves oxidation, methylation, and conjugation, resulting in the formation of pharmacologically inactive metabolites 6.
• The major metabolites of paroxetine are conjugates, which do not compromise its selectivity nor contribute to the clinical response 6.
• The hepatic disposition of paroxetine has been evaluated using sandwich-cultured rat and human hepatocytes, which showed species differences in metabolite profiles and biliary excretion 7.

Enzymes Involved in Paroxetine Metabolism

• CYP2D6 is the primary enzyme involved in paroxetine metabolism, with a high affinity for the drug 5.
• CYP3A4 is also involved in paroxetine metabolism, although to a lesser extent than CYP2D6 5.
• Other enzymes, such as CYP1A2, CYP2C19, and CYP3A5, may also play a role in paroxetine metabolism, although their importance is likely limited 5.

Factors Affecting Paroxetine Metabolism

• The metabolism of paroxetine can be affected by the induction or inhibition of drug-metabolizing enzymes, such as cytochrome P450 isoenzymes 6.
• The pharmacokinetics of paroxetine can also be affected by factors such as age, renal impairment, and hepatic impairment 6.