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Primary metabolism of many drugs is performed by the cytochrome P450 (CYP) family of enzymes. This is a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP enzymes, CYP2D6, is wholly or partially responsible for the hydroxylation or dealkylation (inactivation) of many commonly prescribed drugs such as some analgesics, anticonvulsants, antidepressants, antipsychotics, antiemetics, antihypertensives, antiestrogens, antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants, and sympathomimetics. See Cytochrome P450 2D6 Known Drug Interaction Chart in Special instructions.
The CYP2D6 gene is highly variable with over 100 named alleles. The gene may be deleted, duplicated, and multiplied, and can have multiple sequence variations. In addition, some individuals have genes that are hybrids of CYP2D6 and CYP2D7 pseudogene. Some individuals have altered CYP2D6 gene sequences that result in synthesis of enzyme devoid of catalytic activity, or an enzyme with diminished catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly depending upon the gene variant found on each chromosome. Duplications and multiplications of the CYP2D6 gene may result in ultrarapid metabolism of CYP2D6-metabolized drugs, if active alleles are involved. CYP2D6 genotypes results are used to predict ultrarapid, extensive (normal), intermediate, and poor metabolizer phenotypes for a sample.
Examples of CYP2D6 star alleles
Extensive metabolism (normal)
*2A, gene duplication (depends on allele duplicated)
*2, *9, *10, *14B, *17, *29 and *41
*3, *4, *4N, *5, *6, *7, *8, *11, *12, *13, *14A, *15, *68
Phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample. An ultrarapid metabolizer has more than 2 normally functioning alleles or 2 or more alleles of increased function. An extensive (normal) metabolizer has 2 normally functioning alleles or 1 normally functioning allele and 2 reduced function alleles or 2 normally functioning alleles and a nonfunctional allele in the case of a sample with a duplication. An intermediate metabolizer has 1 normally functioning allele and a nonfunctional allele or 2 reduced function alleles. A poor metabolizer has only nonfunctional alleles. There are instances where a phenotype prediction is not categorical and, in these instances, a range of possible phenotypes will be given. It should be noted that other laboratories may use different phenotype prediction methods as there is no consensus on this in the literature at this time. However, the method used here represents the findings of the majority of literature available at this time.
Dosing drugs that are metabolized through CYP2D6 may require adjustment based on the individual patient's genotype. Patients who are poor metabolizers may require lower than usual doses to achieve optimal response in the case of drugs that are inactivated by the CYP2D6 enzyme and higher than usual doses in the case of drugs that are activated by CYP2D6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2D6 enzyme and lower doses in the case of drugs that are activated by CYP2D6. In the absence of clear guidance from FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism may benefit by switching to another comparable drugs that is not primarily metabolized by CYP2D6 or by therapeutic drug monitoring where applicable.
Overall, this test provides a comprehensive CYP2D6 genotype result for patients, ensuring a more accurate phenotype prediction. This assay has clinical significance for patients taking or considering medications activated (eg, codeine, tramadol, and tamoxifen) or inactivated (eg, antidepressants and antipsychotics) by the CYP2D6 enzyme.
The different tiers associated with the CYP2D6 Cascade will be sequentially initiated until a complete genotype is determined.
Providing information relevant to tamoxifen, psychotropic medications (such as fluoxetine, nortriptyline, paroxetine, and pimozide), codeine, and tramadol, as well as other medications metabolized by CYP2D6
Determining the exact genotype when other methods fail to generate this information or if genotype-phenotype discord is encountered clinically
Identifying exact genotyping when required (eg, drug trials, research protocols)
Identifying novel mutations that may interfere with drug metabolism
A comprehensive interpretive report will be provided that combines the results of all tier testing utilized to obtain the final genotype.
For the CYP2D6 Copy Number Variation assay, the reportable copy number range is 0 to 4 copies for each of the CYP2D6 region assessed.
All alterations detected by sequencing will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations and, where possible, are converted to standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1,2) Variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance.
See Cytochrome P450 2D6 Known Drug Interaction Chart in Special Instructions for the most up-to-date listing.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
CYP2D6 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP2D6 status.
Direct DNA testing will not detect all the known mutations that result in a decreased or inactive CYP2D6 gene. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an ultrarapid, intermediate, or poor metabolizer phenotype.
Other polymorphisms in the primer binding regions can affect the testing, and ultimately, the genotyping assessments made.
A complicating factor in correlating CYP2D6 genotype with phenotype is that many drugs or their metabolites are inhibitors of CYP2D6 catalytic activity. Serotonin-specific reuptake inhibitors (SSRIs), as well as some tricyclic antidepressants (TCAs) and other drugs, may reduce CYP2D6 catalytic activity. Patients with an ultrarapid, extensive, or intermediate metabolizer genotype may have CYP2D6 enzyme activity inhibited by a variety of medications or their metabolites. Among the strongest inhibitors of CYP2D6 are bupropion, cinacalcet, fluoxetine, paroxetine, quinidine, duloxetine, sertraline, terbinafine, amiodarone, and cimetidine, although other drugs are also inhibitors. Consequently, an individual may require a decreased drug dose than predicted by genotyping alone. It is important to interpret the results of testing in the context of other co-administered drugs.
CYP2D6 alleles with "reduced function" may metabolize different drugs at different rates, ranging from near normal to poor, but the literature on this is incomplete at this time.
This test is not designed to provide specific dosing or drug selection recommendations and is to be used as an aid to clinical decision making only. Drug-label guidance should be used when dosing patients with medications regardless of the predicted phenotype.
This test is not for use in assessing for autoimmune hepatitis. Autoantibodies for CYP2D6 enzyme are found in many cases of autoimmune hepatitis; order LKM / Liver/Kidney Microsome Type 1 Antibodies, Serum for autoimmune hepatitis assessment.
A comprehensive interpretive report will be provided.
1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300
2. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available from URL: http://www.cypalleles.ki.se/cyp2d6.htm
3. Black JL 3rd, Walker DL, O'Kane DJ, Harmandayan M: Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction. Drug Metab Dispos 2012;40(1):111-119
4. Goetz MP, Rae M, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312-9318
5. Kircheiner J, Nickchen K, Bauer M, et al: Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004;9:442-473
6. Crews KR, Gaedigk A, Dunnenberger HM, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2011 Feb;91(2):321-326
7. Hicks JK, Swen JJ, Thorn CF, et al: Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013 May:93(5):402-408