Gene Description

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Gene Description

CYP2D6

Cytochrome P450 2D6 (CYP2D6), primarily expressed in the liver, is estimated to be involved in the metabolism of up to 25% of all drugs that are in common use in the clinic.1 CYP2D6 is highly polymorphic. In addition, accurate copy number calling is critical in determining the CYP2D6 phenotype as the variation in copy number might lead to increased or no function compared to normal.  The Clinical Pharmacogenetics Implementation Consortium (CPIC) has released guidelines for codeine, selective serotonin reuptake inhibitors, tricyclic antidepressants, tamoxifen, ondansetron and tropisetron based on CYP2D6 metabolizer status.

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants (TCAs), including imipramine, amitriptyline, trimipramine and clomipramine, and of the secondary amine TCA nortriptyline, are used to treat several disease states including depression, obsessive-compulsive disorder, and neuropathic pain in addition to migraine prophylaxis. There is substantial evidence linking CYP2C19 and CYP2D6 genotypes to the interpatient variability in TCA side effects and pharmacokinetic profiles. Using the pharmacogenetic information of the two genes to guide TCA dosing and selection could potentially improve clinical outcome and reduce adverse events2 as well as treatment failures.

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. Polymorphisms on CYP2D6 and CYP2C19 can influence the metabolism of SSRI, and thereby affecting drug efficacy and safety. Utilizing pharmacogenetics results to guide SSRI therapy could potentially improve the treatment responses and reduce the occurrence of adverse events3 as well as treatment failures.

Codeine

Codeine is indicated for the relief of mild to moderately severe pain. The analgesic properties of codeine stem from its conversion to morphine by the hepatic CYP2D6, and hence the polymorphisms of CYP2D6 affect the efficacy and safety of codeine. The CPIC guideline recommends using alternative analgesics to codeine in patients, who are CYP2D6 poor or ultra-rapid metabolizers.4

Ondansetron and tropisetron

Ondansetron and tropisetron are indicated for prevention of nausea and vomiting, induced by chemotherapy, radiation, and operation. Ondansetron and tropisetron are metabolized into inactive metabolites by CYP2D6, and other CYP enzymes. CYP2D6 ultra-rapid metabolizer (UMs) are associated with decreased antiemetic effect (i.e. vomiting) of ondansetron and tropisetron. The CPIC guideline recommends alternative drug that is not predominantly metabolized by CYP2D6, for the CYP2D6 UMs.5

Tamoxifen

Tamoxifen is the most prescribed selective estrogen receptor modulator (SERM) for breast cancer expressing estrogen receptors or progesterone receptors in the US. Tamoxifen is transformed by CYP2D6 into the metabolites with greater potency. CYP2D6 poor metabolizers and intermediate metabolizers are expected to have higher risks of recurrence and worse event-free survival compared to normal metabolizers. The CPIC guideline provides dosing recommendations for tamoxifen based on CYP2D6 phenotypes.6

Atomoxetine

Atomoxetine is a nonstimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). An estimated 6.1 million children between the ages of 2 and 17 years received a diagnosis of ADHD in the US7. Likely due to increased exposure to the parent drug in the poor metabolizers (PMs), favorable treatment response and side effects are both reported among the CYP2D6 PMs compared to non-PMs. The FDA-approved drug label for atomoxetine (STRATTERA) recommends a dose adjustment in children or adolescents who are CYP2D6 poor metabolizers, or who are administered strong CYP2D6 inhibitors. Additionally, the label notes a few adverse events that occurred more frequently in CYP2D6 poor metabolizers than extensive metabolizers in clinical trials8. The CPIC guideline provides dosing recommendations for atomoxetine based on CYP2D6 phenotypes9.

 

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References
  1. Owen RP, et al. Cytochrome P450 2D6. Pharmacogenet Genom. 2009.
  2. Hicks JK, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update. Clin Pharmacol Ther. 2017;102(1):37-44.
  3. Hicks JK, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-34.
  4. Crews KR, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. Clin Pharmacol Ther. 2014;95(4):376-82.
  5. Bell GC, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Use of Ondansetron and Tropisetron. Clin Pharmacol Ther. 2017;102(2):213-18.
  6. Goetz MP, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018;103(5):770-77.
  7. Danielson, ML., et al., Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents, 2016. J. Clin. Child. Adolesc. Psychol. 47, 199–212. 2018.
  8. Annotation of FDA Label for atomoxetine and CYP2D6, PharmGKB, 09/2019
  9. Brown, JT., et al., Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy. Clin Pharmcol Ther. 2020. ePub ahead