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Reference Guide
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CYP2D6
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CYP2D6

CYP2D6 encodes a key enzyme involved in the metabolism of many commonly prescribed drugs, including antidepressants, beta-blockers, opioids, and tamoxifen. 

Genetic variations in CYP2D6 influence individual drug response, classifying people as poor, intermediate, normal, or ultrarapid metabolizers, which affects medication efficacy, safety, and dosing recommendations.

What is CYP2D6?

The CYP2D6 gene, located on chromosome 22q13.2, encodes cytochrome P450 2D6, an enzyme responsible for metabolizing approximately 21% of commonly prescribed drugs. These include antidepressants, antipsychotics, beta-blockers, opioids, and tamoxifen. 

Despite comprising only 2-4% of hepatic CYP enzymes, CYP2D6 plays a critical role in drug metabolism, directly impacting therapeutic efficacy and safety.

CYP2D6 activity varies significantly due to genetic polymorphisms, which classify individuals into poor (PM), intermediate (IM), normal (NM), and ultrarapid (UM) metabolizers. These variations influence how quickly or effectively drugs are metabolized, affecting treatment success, risk of toxicity, and appropriate dosing strategies. 

Pharmacogenetic testing can help identify a patient’s metabolizer status, allowing for personalized medication adjustments to improve outcomes. 

Regulatory bodies like the FDA and the Clinical Pharmacogenetics Implementation Consortium (CPIC) provide guidelines for optimizing drug therapy based on CYP2D6-related metabolism.

CYP2D6 Genetic Variability and Metabolizer Phenotypes

CYP2D6 is highly polymorphic, with over 130 known allelic variants. These variations influence enzyme activity and classify individuals into four main metabolizer phenotypes, which are described by their specific activity scores (AS):

  • Poor Metabolizers (PMs) (AS = 0) → No functional enzyme activity, leading to drug accumulation and increased toxicity risk.
  • Intermediate Metabolizers (IMs) (AS = 0.25 - 1) → Reduced enzyme function, resulting in slower drug clearance.
  • Normal Metabolizers (NMs) (AS = 1.25 - 2.25) → Standard drug metabolism and expected therapeutic response.
  • Ultra-rapid Metabolizers (UMs) (AS > 2.25) → Increased enzyme activity due to gene duplication, leading to reduced drug efficacy or excessive drug breakdown.

CYP2D6 Mutations

Genetic mutations in CYP2D6 affect how individuals metabolize medications. Some common mutations include:

These variations are clinically significant, influencing drug dosing, efficacy, and safety.

Conditions Associated with CYP2D6 Mutations

CYP2D6 genetic polymorphisms impact drug metabolism in various therapeutic areas, including:

Pain Management

Opioids (Codeine, Tramadol, Oxycodone)

  • UMs: increased risk of opioid toxicity (excessive drug activation).
  • PMs: reduced pain relief (inability to convert prodrugs into active metabolites).

Psychiatry and Neurology

Antidepressants (SSRIs, TCAs, MAOIs)

Antipsychotics (Risperidone, Haloperidol)

PMs → Increased drug accumulation, higher risk of movement disorders.

Cardiology

Beta-Blockers (Metoprolol, Propranolol)

  • UMs: reduced therapeutic effect.
  • PMs: increased drug levels, risk of bradycardia.

Oncology

Tamoxifen (Breast Cancer Treatment)

Autoimmune and Gastrointestinal Disorders

Immunosuppressants (e.g., Tacrolimus)

Why Test for CYP2D6?

Pharmacogenetic testing can help optimize drug therapy by predicting individual responses to medications. The FDA recognizes CYP2D6 as a key pharmacogenetic biomarker, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) provides guidelines for this.

Challenges in Testing

There are several potential challenges in testing CYP2D6, including:

  • Structural Variability: gene duplications, deletions, and hybrids may complicate testing.
  • Assay Differences: not all labs test for complex CYP2D6 variants.
  • Phenoconversion: drug interactions (e.g., CYP2D6 inhibitors like fluoxetine, paroxetine) can alter expected metabolizer status.

CYP2D6 and Drug Interactions

CYP2D6 activity is susceptible to inhibition or induction by medications and natural compounds:

Inhibitors (Reduce CYP2D6 Activity → Increased Drug Levels)

The following drugs are known to reduce CYP2D6 activity:

  • SSRIs (Fluoxetine, Paroxetine)
  • Antifungals (Ketoconazole, Itraconazole)
  • Cardiovascular Drugs (Amiodarone, Quinidine)

Inducers (Increase CYP2D6 Activity → Decreased Drug Levels)

The following drugs may increase CYP2D6 activity:

  • Rifampin
  • Dexamethasone

CYP2D6 and Cannabidiol (CBD)

CBD inhibits CYP2D6, which may increase the effects and side effects of drugs like antidepressants, beta-blockers, opioids, and tamoxifen. Patients using both CBD and CYP2D6-metabolized medications may require dose adjustments.

Test Procedure and Interpretation

Testing for CYP2D6 is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for CYP2D6 genetic testing are considered to be without mutations that can alter the activity of the CYP2D6 proteins.

Clinical Implications of Positive CYP2D6 Mutations

CYP2D6 mutations have significant clinical implications, influencing drug metabolism and therapeutic outcomes. 

Poor metabolizers (PMs) are at risk for adverse drug reactions due to reduced clearance of CYP2D6 substrates, while ultrarapid metabolizers (UMs) may experience subtherapeutic drug levels, leading to treatment failure. Intermediate metabolizers (IMs) often require dose adjustments, whereas normal metabolizers (NMs) generally process medications as expected. 

Given the variability in CYP2D6 function across populations, pharmacogenetic testing can guide personalized prescribing, optimizing efficacy while minimizing risks.

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See References

Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002 Feb;53(2):111-22. doi: 10.1046/j.0306-5251.2001.01548.x. PMID: 11851634; PMCID: PMC1874287.

Cannabidiol: MedlinePlus Supplements. (2019). Medlineplus.gov. https://medlineplus.gov/druginfo/natural/1439.html

CPIC® Guideline for Opioids and CYP2D6, OPRM1, and COMT. (n.d.). Cpicpgx.org. https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/

FDA. (2020). Table of Pharmacogenetic Associations. FDA. https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations

Kane M. CYP2D6 Overview: Allele and Phenotype Frequencies. 2021 Oct 15 [Updated 2025 Jan 17]. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574601/

Pratt VM, Cavallari LH, Del Tredici AL, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, van Schaik RHN, Whirl-Carrillo M, Weck KE. Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy. J Mol Diagn. 2021 Sep;23(9):1047-1064. doi: 10.1016/j.jmoldx.2021.05.013. Epub 2021 Jun 10. PMID: 34118403; PMCID: PMC8579245.

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