What drugs inhibit CYP2D6 (cytochrome P450 2D6)?

Drugs that Inhibit CYP2D6

Paroxetine, fluoxetine, bupropion, and quinidine are the most potent inhibitors of CYP2D6, while drugs like sertraline, citalopram, venlafaxine, and escitalopram are mild inhibitors. 1, 2, 3

Strong CYP2D6 Inhibitors

• Paroxetine - Considered one of the most potent inhibitors of CYP2D6, comparable to quinidine in its inhibitory strength 3
• Fluoxetine - Strong inhibitor with prolonged effect due to its active metabolite norfluoxetine, which also inhibits CYP2D6 and has a long half-life 1, 4
• Bupropion - Can convert CYP2D6 extensive metabolizers to poor metabolizer phenotype, indicating potent inhibition 5, 2
• Quinidine - Reference standard for potent CYP2D6 inhibition 6, 3
• Fluvoxamine - Potent inhibitor of CYP2D6 7

Moderate to Mild CYP2D6 Inhibitors

• Sertraline - Considered a mild CYP2D6 inhibitor compared to paroxetine and fluoxetine 6, 3
• Citalopram - Mild inhibitor of CYP2D6 6
• Venlafaxine - Mild inhibitor of CYP2D6 6
• Escitalopram - Mild inhibitor of CYP2D6 6
• Duloxetine - Moderate inhibitor of CYP2D6 6

Clinical Significance of CYP2D6 Inhibition

CYP2D6 inhibition is clinically significant because it affects the metabolism of many commonly prescribed medications:

• Antidepressants - Tricyclic antidepressants (TCAs), venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline 5, 3
• Antipsychotics - Haloperidol, risperidone, thioridazine, phenothiazines 1, 5
• Beta-blockers - Metoprolol and other beta-blockers 5, 3
• Antiarrhythmics - Type 1C antiarrhythmics such as propafenone and flecainide 6, 5
• Opioids - Codeine and other opioids that require CYP2D6 activation 3

Special Considerations in Clinical Practice

Tamoxifen Metabolism

• Tamoxifen requires CYP2D6 for conversion to its active metabolite endoxifen 6
• Strong CYP2D6 inhibitors (paroxetine, fluoxetine) can significantly reduce tamoxifen efficacy 6
• If antidepressant therapy is needed in patients taking tamoxifen, mild CYP2D6 inhibitors (sertraline, citalopram, venlafaxine, escitalopram) are preferred over potent inhibitors 6

Duration of Inhibition

• Fluoxetine's inhibition of CYP2D6 can persist for weeks after discontinuation due to the long half-life of its active metabolite norfluoxetine 4, 3
• This prolonged effect should be considered when switching medications that are CYP2D6 substrates 1, 4

Genetic Considerations

• Approximately 7-10% of the population are poor CYP2D6 metabolizers due to genetic polymorphisms 6
• CYP2D6 inhibitors can convert normal (extensive) metabolizers to a phenotypic poor metabolizer status 2

Practical Recommendations

• When prescribing multiple medications, check for potential CYP2D6-mediated interactions 1, 5
• For patients on tamoxifen therapy requiring antidepressants, prefer mild CYP2D6 inhibitors 6
• When initiating therapy with medications that are predominantly metabolized by CYP2D6, start at the lower end of the dosing range if the patient is taking a CYP2D6 inhibitor 1
• Consider that inhibition of CYP2D6 by fluoxetine may persist for weeks after discontinuation 4, 3