What are CYP2D6 (cytochrome P450 2D6) inhibitors?

From the Guidelines

CYP2D6 inhibitors, such as fluoxetine and paroxetine, should be used with caution due to their potential to increase the blood levels of CYP2D6 substrates, leading to adverse effects or toxicity, as evidenced by studies showing a 419% increase in CYP2D6 metabolism when treated with paroxetine 1. When considering the use of CYP2D6 inhibitors, it is essential to be aware of their potential interactions with other medications.

• Strong CYP2D6 inhibitors include fluoxetine, paroxetine, bupropion, and quinidine, while moderate inhibitors include duloxetine, sertraline, and terbinafine.
• Common CYP2D6 substrates include certain antidepressants, antipsychotics, beta-blockers, and opioid analgesics like codeine and tramadol.
• Genetic variations in the CYP2D6 enzyme can also affect how individuals respond to medications, with some people naturally having reduced or enhanced enzyme activity, further complicating medication management when CYP2D6 inhibitors are involved, as discussed in the context of pharmacogenetic guidelines for antidepressants 1. The importance of considering these interactions is highlighted by the fact that fatalities associated with genotyping are increasingly recognized in the forensic literature 1.
• In clinical practice, it is crucial to check for potential drug interactions involving CYP2D6 inhibitors and to consider dose adjustments or alternative medications that do not rely on CYP2D6 metabolism.
• The use of pharmacogenetic guidelines, such as those outlined for antidepressants primarily metabolized by CYP2D6 and CYP2C19, can help reduce adverse effect toxicity profiles and increase response rates and overall effectiveness 1.

From the FDA Drug Label

Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1. 4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.

Paroxetine is a CYP2D6 inhibitor. It may significantly inhibit the activity of this isozyme, leading to increased plasma concentrations of drugs that are metabolized by CYP2D6, such as desipramine, risperidone, and atomoxetine.

• Key points:
  • Paroxetine inhibits CYP2D6 activity
  • Concomitant use with CYP2D6 substrates may require dosage adjustments
  • Increased plasma concentrations of CYP2D6 substrates may occur when coadministered with paroxetine 2

From the Research

CYP2D6 Inhibitors

• CYP2D6 is an enzyme that plays a crucial role in the metabolism of many drugs, including antidepressants and antipsychotics 3, 4.
• Inhibitors of CYP2D6 can increase the levels of these drugs in the body, leading to increased risk of adverse effects 4.
• Examples of CYP2D6 inhibitors include:
  • Paroxetine, which has a high potential for drug interactions with CYP2D6-dependent drugs 4.
  • Fluoxetine, which can inhibit CYP2D6 and increase the levels of other drugs that are metabolized by this enzyme 3, 4.
  • Other selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine, which can also inhibit CYP2D6, although to a lesser extent than paroxetine and fluoxetine 4.

Clinical Implications

• The use of CYP2D6 inhibitors can have significant clinical implications, including increased risk of adverse drug interactions and reduced efficacy of certain drugs 3, 4.
• Patients taking CYP2D6 inhibitors may require dose adjustments or alternative treatments to minimize the risk of adverse effects 3, 4.
• Genetic polymorphisms in the CYP2D6 gene can also affect the metabolism of drugs and increase the risk of adverse effects 5, 6.

Drug Interactions

• CYP2D6 inhibitors can interact with a wide range of drugs, including:
  • Tricyclic antidepressants, which can have increased levels and adverse effects when co-administered with CYP2D6 inhibitors 4.
  • Antipsychotics, which can also have increased levels and adverse effects when co-administered with CYP2D6 inhibitors 4.
  • Other drugs that are metabolized by CYP2D6, such as codeine and beta-blockers 4.

Genetic Polymorphisms

• Genetic polymorphisms in the CYP2D6 gene can affect the metabolism of drugs and increase the risk of adverse effects 5, 6.
• Patients with reduced function variants of the CYP2D6 gene may require dose adjustments or alternative treatments to minimize the risk of adverse effects 5.
• The impact of CYP2D6 polymorphisms on drug metabolism can be significant, and genetic testing may be useful in predicting individual dose requirements 5, 6.