Cytochrome P450 2D6 (CYP2D6)

PG4KDS Implemented Genes

CYP2D6 is an enzyme that is responsible for breaking down (metabolizing) many of the drugs that are commonly used today. Some medications, such as codeine, require activation by CYP2D6 in order for the medication to be effective. Other drugs, such as tricyclic antidepressants (e.g., amitriptyline and imipramine), are metabolized to forms that are not active and are more easily eliminated from the body. There are many other medications that may be affected by CYP2D6 (see this link:  http://www.pharmgkb.org/search/annotatedGene/cyp2d6/index.jsp).

For some of these medications, it is not absolutely clear what changes in dosing should be driven by CYP2D6 genotype; in this study, we will build up the “rules” to decide which medications to link to the priority genotypes. Over 100 known differences exist in the gene for CYP2D6. These differences in the CYP2D6 gene lead to the production of an enzyme that ranges from completely inactive to overactive. A system designed to classify patients into 4 genotype metabolizer categories based on the ability of their CYP2D6 to break down drugs is used by clinicians to help guide drug therapy decisions.

Priority genotypes

  • Poor metabolizers – These patients have little or no working CYP2D6. About 1 in 10 people are poor metabolizers.
    • Drugs we recommend to avoid:
      • Codeine. Codeine has no analgesic effect in these patients. Other pain medications such as a non-opioid agent, morphine, HYDROmorphone (e.g.: Dilaudid®) or acetaminophen/hydroCODONE (e.g.: Lortab®, Vicodin®) are recommended.
      • Tramadol. Tramadol has little or no analgesic effect in these patients. Other pain medications such as a non-opioid agent, morphine, HYDROmorphone (e.g.: Dilaudid®) or acetaminophen/hydroCODONE (e.g.: Lortab®, Vicodin®) are recommended.
      • Oxycodone: Oxycodone may have little analgesic effect in these patients. Other pain medications such as a non-opioid agent, morphine, HYDROmorphone (e.g.: Dilaudid®) or acetaminophen/hydroCODONE (e.g.: Lortab®, Vicodin®) are recommended.
      • Amitriptyline. Blood levels of amitriptyline and its active metabolite are expected to be high in these patients, and side effects are likely. If amitriptyline is used in a poor metabolizer, lower doses may be needed, and blood levels of amitriptyline and its metabolite can be monitored. Amitriptyline dosing is also affected by the CYP2C19 genotype test result.
      • Fluoxetine. Blood levels of fluoxetine are expected to be high in these patients, and side effects are likely. Lower doses may be needed.
      • Paroxetine. Blood levels of paroxetine are expected to be high in these patients, and side effects are likely. Lower doses may be needed.
    • Other drugs may be affected. The PG4KDS study will evaluate what should be done for the dosing of these other drugs.
  • Ultra rapid metabolizers – These subjects have multiple copies of the CYP2D6 gene, and therefore greater-than-normal CYP2D6 function. About 2 in 100 people are ultra rapid metabolizers.
    • Drugs we recommend to avoid:
      • Codeine. Codeine may cause serious side effects (respiratory depression, confusion, lethargy) in these patients. Other pain medications such as a non-opioid agent, morphine, HYDROmorphone (e.g.: Dilaudid®) or acetaminophen/hydroCODONE (e.g.: Lortab®, Vicodin®) are recommended.
      • Oxycodone: Oxycodone may cause serious side effects (respiratory depression, confusion, lethargy) in these patients. Other pain medications such as a non-opioid agent, morphine, HYDROmorphone (e.g.: Dilaudid®) or acetaminophen/hydroCODONE (e.g.: Lortab®, Vicodin®) are recommended.
      • Tramadol. Tramadol may cause serious side effects (respiratory depression, confusion, lethargy) in these patients. Other pain medications such as a non-opioid agent, morphine, HYDROmorphone (e.g.: Dilaudid®) or acetaminophen/hydroCODONE (e.g.: Lortab®, Vicodin®) are recommended.
      • Amitriptyline. Blood levels of amitriptyline and its active metabolites are likely to be low; therefore these patients may not respond well to this medicine. Amitriptyline dosing is also affected by the CYP2C19 genotype test result.
      • Fluoxetine. Blood levels of fluoxetine and its active metabolite are likely to be low; therefore these patients may not respond well to this medicine.
      • Paroxetine. Blood levels of paroxetine are likely to be low; therefore these patients may not respond well to this medicine.
      • Ondansetron. Ondansetron may not be as effective for management of nausea and vomiting in these patients. Other antiemetics not metabolized by CYP2D6 (such as granisetron) are recommended.
    • Other drugs may be affected. The PG4KDS study will evaluate what should be done for the dosing of these other drugs.

Routine genotypes. We do not routinely adjust medicine doses based on the following genotypes, except in rare instances:

  • Intermediate metabolizers – These subjects metabolize drugs at a rate somewhere between the poor and extensive metabolizers. About 1 in 10 people are intermediate metabolizers.
    • Drugs we recommend to adjust the dose:
      • Amitriptyline. Blood levels of amitriptyline and its active metabolite may be high in these patients, and side effects are possible. If amitriptyline is used in an intermediate metabolizer, lower doses may be needed, or blood levels of amitriptyline and its metabolites may need to be monitored. Amitriptyline dosing is also affected by the CYP2C19 genotype test result.
  • Extensive metabolizer – These subjects have normal CYP2D6 function. About 8 in 10 people are extensive metabolizers.


More information for patients...

"Do you know..." info sheet: Cytochrome P450 2D6 (CYP2D6) and medicines

More information for healthcare professionals, visit www.pharmGKB.org.

Legal Disclaimer: This page is intended to provide implementers with guidance on establishing a clinical pharmacogenetic program at their institution. Information contained on this page is for information and educational purposes only. Although reasonable efforts have been made to ensure that the information provided on this page is current, complete and, where appropriate, based on scientific evidence, St. Jude Children's Research Hospital makes no assurances as to whether the provided information will at all times be current or complete. St. Jude Children's Research Hospital, in offering this document, is not providing medical advice or offering a consultative opinion, and is not establishing a treatment relationship with any given individual. You, therefore, should not substitute information contained herein for your own professional judgment, nor should you rely on information provided herein in rendering a diagnosis or choosing a course of treatment for a particular individual.