Cytochrome P450 2D6 (CYP2D6) Comprehensive Cascade, Blood
Providing information relevant to tamoxifen 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 variants that may interfere with drug metabolism
Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request
Approximately 94% to 96% of individuals will not need additional CYP2D6 testing beyond tier 1. Based on tier 1 test sensitivity and CYP2D6 variant carrier frequencies, approximately 4% to 6% of Caucasians require testing through tier 2 or 3 in order to determine the comprehensive genotype (the frequency may be higher or lower in other ethnic groups). Testing through tier 3 allows for the detection of all common CYP2D6 variants (eg, *2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) and rarer (including novel) alleles such as *11, *12, *14 and *15. Unitary and tandem CYP2D7-2D6 (*13) alleles and CYP2D6-2D7 (eg, *4N and *36) alleles can also be detected. Furthermore, the actual alleles that are duplicated or multiplied can be determined in most cases.
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
The cytochrome P450 (CYP) family of enzymes is responsible for primary metabolism of many drugs. CYP450s are oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of the CYP enzymes, CYP2D6, is wholly or partially responsible for the metabolism 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, sympathomimetic and other drug classes.
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 the CYP2D7 pseudogene. Some individuals have altered CYP2D6 variants 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. CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict ultrarapid, ultrarapid to extensive (normal), extensive (normal), extensive (normal) to intermediate, intermediate, intermediate to poor, and poor metabolizer phenotypes. (see Table 1)
Table 1. Enzyme Activity of Individual Star Alleles
Examples of CYP2D6 star alleles
Extensive metabolism (normal)
*2, *9, *10, *14B, *17, *29 and *41
No or null activity
*3, *4, *4N, *5, *6, *7, *8, *11, *12, *13, *14A, *15, *68
CYP2D6 phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample. (see Table 2)
Table 2. Phenotype Assignment of CYP2D6
Predicted Drug Metabolizer Phenotype**
Without Gene Duplication
With Gene Duplication
2 increased activity alleles
3 normal and/or increased activity alleles
EM to UM
A combination of 1 normal activity allele with 1 increased activity allele
A combination of 2 normal alleles with one decreased activity allele
2 normal activity alleles; a combination of one increased activity allele with one decreased allele
A combination of 2 normal alleles with 1 null allele; a combinantion of 1 normal allele with 2 decreased activity alleles
IM to EM
A combination of 1 normal activity allele with 1 decreased activity allele; a combination of 1 increased activity with 1 null allele
1 increased activity allele with 2 null alleles, 3 decreased activity alleles
1 normal activity allele with 1 null activity allele; 2 decreased activity alleles
1 normal allele with 2 or more null alleles, 2 decreased activity alleles with 1 null allele.
PM to IM
A combination of 1 decreased activity allele with 1 null allele
1 decreased activity allele with 2 null allele
Only null alleles detected
* Phenotyping was derived from the Human Cytochrome P450 (CYP) Allele Nomenclature Committee website and the PharmGKB website for the related Clinical Pharmacogenetics Implementation Consortium guidelines.
**Ultra-Rapid Metabolizer, UM; Extensive Metabolizer, EM; Intermediate Metabolizer, IM; Poor Metabolizer, PM
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 at this time. However, the method used here represents the findings of the majority of literature available at this time. Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2D6 *1/*1.
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.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
A comprehensive interpretive report will be provided.
A comprehensive interpretive report will be provided that combines the results of all tier testing utilized to obtain the final genotype.
The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1)
For the CYP2D6 Copy Number Variation assay, the reportable copy number range is 0 to 4 copies for each of the CYP2D6 region assessed.
Novel 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.
For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.
CYP2D6 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP2D6 status.
This method may not detect all CYP2D6 variants that result in altered CYP2D6 activity. Therefore, absence of a detectable gene variant does not rule out the possibility that a patient has an altered CYP2D6 metabolism due to other CYP2D6 variants that cannot be detected with this method. Furthermore, when two or more gene variants are identified, the cis-/trans- status (whether the variants are on the same or opposite chromosomes) is not always known. Rare variants may be present and could lead to false negative or positive results. If results obtained do not match the clinical findings (phenotype), additional testing should be considered.
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. 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.
Karolinska Database for CYP2D6 gene: http://www.cypalleles.ki.se/cyp2d6.htm
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at URL: http://www.cypalleles.ki.se/cyp2d6.htm
2. 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
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