Test ID: 2D6O
Cytochrome P450 2D6 Genotype, Saliva

Identifying patients who are poor or extensive metabolizers of antidepressant drugs metabolized by CYP2D6

Adjusting dosages for antidepressant drugs that are metabolized by CYP2D6

• Informed Consent for Genetic Testing
• Multiple Saliva Genotype Tests

Polymerase Chain Reaction (PCR) with Allele-Specific Primer Extension (ASPE)/Bead Hybridization with Fluorescence Detection

(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)

Multiple saliva genotype tests can be performed on a single specimen after a single extraction. See Multiple Saliva Genotype Tests in Special Instructions for a list of tests that can be ordered together.

Container/Tube: Oragene DNA Self-Collection Kit (Supply T651)

Specimen Volume: Full tube

Collection Instructions:

1. Fill tube to line.

2. Send in original container per kit instructions.

Additional Information:

1. Cytochrome P450 Patient Education Brochure (Supply T526) is available upon request.

2. Liver transplants will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 for instructions.

Forms: New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.

Primary metabolism of many drugs is performed by cytochrome P450 (CYP), 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 of many commonly prescribed drugs such as analgesics, anticonvulsants, antidepressants, antiemetics, antihypertensives, antiestrogens, antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants, and sympathomimetics. The current clinical application of this test is focused on the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). Amitriptyline, clomipramine, desipramine, imipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine are metabolized by CYP2D6.

CYP2D6-mediated drug metabolism is highly variable. Some individuals have altered CYP2D6 gene sequences that result in synthesis of enzyme devoid of catalytic activity, or in enzyme with diminished catalytic activity. These individuals metabolize SSRIs and TCAs poorly. Duplication of the functional CYP2D6 gene has been observed, which may result in ultrarapid metabolism of SSRIs and other drugs. Up to 13 copies of CYP2D6 have been reported.

Dosing of SSRIs and TCAs 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. Patients who are ultrarapid metabolizers may benefit from increased doses. Patients with either ultrarapid or poor metabolism also may benefit by conversion to other comparable drugs that are not primarily metabolized by CYP2D6 or by therapeutic drug monitoring where applicable.

A number of specific polymorphisms have been found in the CYP2D6 gene that result in enzymatic deficiencies. The frequency of these polymorphisms varies within the major ethnic groups. CYP2D6 polymorphisms that produce poor metabolizers are found with frequencies of 7% to 10% in Caucasians, 2% in Africans and African Americans, and 1% in Asians. Individuals without inactivating polymorphisms, deletions, or duplications have the phenotype of an extensive drug metabolizer (normal) and are designated as CYP2D6*1/*1.

All of the identified polymorphisms associated with CYP2D6 are autosomal recessive. Consequently, only individuals who are homozygous or compound heterozygous for these polymorphisms are poor metabolizers. Individuals who are heterozygous, with 1 normal gene and 1 polymorphic gene, will have metabolism intermediate between the extensive (normal) and poor metabolizers.

The following information outlines the relationship between the polymorphisms detected in this assay and the effect on the activity of the enzyme produced by that allele:

A complicating factor in correlating CYP2D6 genotype with phenotype is that many drugs or their metabolites are inhibitors of CYP2D6 catalytic activity. SSRIs, as well as some TCAs and other xenobiotics, may reduce or increase CYP2D6 catalytic activity. Consequently, an individual may require a dosing decrease greater than predicted based upon genotype alone. It is important to interpret the results of testing in the context of other coadministered drugs.

An interpretive report will be provided.

An interpretive report will be provided.

Based on the test sensitivity and currently available CYP2D6 polymorphism carrier frequencies, persons of Caucasian descent who tested negative for the above polymorphisms would be estimated to have a <1.4% residual risk for carrying 1 or more copies of an undetected poor metabolizer allele. This residual risk may be higher or lower in other ethnic groups. The frequency of polymorphisms causing poor metabolism is highest in the Caucasian population and lower in African-Americans and Asians. Patients with an extensive (normal) or intermediate metabolizer genotype may have CYP2D6 enzyme activity inhibited by a variety of medications, or their metabolites. The following is a partial listing of drugs known to affect CYP2D6 activity as of the date of this report.

Drugs known to increase CYP2D6 activity:

-Dexamethasone

-Rifampin

Coadministration of these drugs will increase the rate of excretion of CYP2D6 metabolized drugs, reducing that drug's effectiveness.

Drugs known to decrease CYP2D6 activity:

-Amiodarone

-Bupropion

-Celecoxib

-Clomipramine

-Chlorpheniramine

-Chlorpromazine

-Cimetidine

-Citalopram

-Cinacalcet

-Cocaine

-Dexmedetomidine

-Diphenhydramine

-Doxepine

-Duloxetine

-Escitalopram

-Fluoxetine

-Haloperidol

-Halofantrine

-Hydroxyzine

-Indinavir

-Levomepromazine

-Methadone

-Metochlopramide

-Moclobemide

-Paroxetine

-Perazine

-Pergolide

-Perphenazine

-Pimozide

-Quinidine

-Ranitidine

-Ritonavir

-Sertraline

-Tegaserod

-Terbinafine

-Ticlopidine

Coadministration will decrease the rate of metabolism of CYP2D6-metabolized drugs, increasing the possibility of toxicity.

Drugs that undergo metabolism by CYP2D6:

-Alprenolol

-Amitriptyline

-Amphetamine

-Aripiprazole

-Atomoxetine

-Bufuradol

-Carvedilol

-Chlorpheniramine

-Chlorpromazine

-Clomipramine

-Codeine

-Debrisoquine

-Desipramine

-Dextromethorphan

-Dexfenfluramine

-Diltiazem

-Disopyramide

-Donepezil

-Duloxetine

-Encainide

-Flecainide

-Fluoxetine

-Fluvoxamine

-Haloperidol

-Iloperidone

-Imipramine

-Labetalol

-Lidocaine

-Metoclopramide

-Methoxyamphetamine

-Metoprolol

-Mexilitine

-Minaprine

-Mirtazapine

-Nebivolol

-Nortriptyline

-Oxycodone

-Ondansetron

-Paroxetene

-Pergolide

-Perhexiline

-Perphenazine

-Promethazine

-Phenformin

-Pimozide

-Propafenone

-Propranolol

-Respirdone

-Sertraline

-Sparteine

-Tamoxifen

-Thioridazine

-Tegaserod

-Timolol

-Tramadol

-Venlafaxine

-Zuclopenthixol

Coadministration may decrease the rate of elimination of other drugs metabolized by of CYP2D6.

Drug-drug interactions and drug-metabolite inhibition or activation must be considered when dealing with heterozygous individuals. Drug-metabolite inhibition occurs frequently with selective serotonin reuptake inhibitors and tricyclic antidepressants, resulting in inhibition of residual functional CYP2D6 catalytic activity. Each report will include a list of commonly prescribed drugs, by drug class, that are known to alter CYP2D6 activity. This list includes only those drugs for which established, peer-reviewed literature substantiates the effect. The list provided is not all-inclusive.

CYP2D6 activity also is dependent upon hepatic and renal function status, as well as age. Patients also may develop toxicity if hepatic or renal function is decreased. Drug metabolism also is known to decrease with age. It is important to interpret the results of testing and dose adjustments in the context of renal and hepatic function and age.

Direct DNA testing will not detect all the known mutations that result in decreased or inactive CYP2D6. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an intermediate or poor metabolizer phenotype.

This test does not detect polymorphisms other than those listed. Gene duplications may occur by other mechanisms and may not be detected. Other polymorphisms in the primer binding regions can affect the testing, and ultimately, the genotyping assessments made. Testing may reflex to DNA sequencing to resolve difficult genotypes or to confirm interpretations.

Patients with an extensive or intermediate metabolizer genotype may have CYP2D6 enzyme activity inhibited by a variety of medications or their metabolites, including many tricyclic antidepressants, selective serotonin reuptake inhibitors, many histamine H-2 receptor antagonists, amiodarone, celecoxib, cimetidine, cocaine, methadone, quinidine, and ritonavir, as well as several other drugs. Treatment with drugs that are inhibitors of CYP2D6, or produce inhibitors through metabolism, may generate a poor metabolizer phenotype in an individual who has an extensive or intermediate metabolizer genotype.

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.

The drug application that we currently support for testing and interpretation is for the treatment of depression and other psychiatric disorders.

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/80387 Liver/Kidney Microsome Type 1 Antibodies, Serum for autoimmune hepatitis assessment.

If considering treatment with tamoxifen, order 2D6TO/60340 Cytochrome P450 2D6 Genotyping for Tamoxifen Hormonal Therapy, Saliva.

1. Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A: Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002 Feb;53(2):111-122

2. Lundqvist E, Johansson I, Ingelman-Sundberg M: Genetic mechanisms for duplication and multiduplication of the human CYP2D6 gene and methods for detection of duplicated CYP2D6 genes. Gene 1999 Jan 21;226(2):327-338

3. Kirchheiner J, Brosen K, Dahl ML, et al: CYP2D6 and CYPSC19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psych Scand 2001 Sept;104(3):173-192

4. Lam YWF, Gaedigk A, Ereshefsy L, et al: CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy 2002;22:1001-1006

Genomic DNA is extracted from saliva. Direct polymorphism analysis for CYP2D6 gene is performed after (multiplex) PCR and allele-specific primer extension with Luminex Molecular Diagnostics’ proprietary Universal Tag sorting system on the Luminex 100 xMAP platform. A genotype is assigned based on the allele-specific fluorescent signals that are detected. (Unpublished Mayo method)

Monday, Thursday; 8 a.m.

81226-CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)