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Interpretive Handbook

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Test 60439 :
Cytochrome P450 2C19 Genotype by Sequence Analysis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Primary metabolism of many drugs is performed by cytochrome P450 (CYP450), a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP450 enzymes, CYP2C19, metabolizes a wide variety of drugs including antiulcer drugs such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam. It is also partially responsible for metabolizing other drugs such as the beta-blocker propranolol and the antidepressants fluvoxamine and fluoxetine. It is also involved in the activation of the anticoagulant clopidogrel.

 

CYP2C19 drug metabolism is variable among individuals. Some individuals have CYP2C19 genetic variants that result in enzyme with diminished or absent catalytic activity (ie, poor metabolizers). The frequency of these variants (aka polymorphisms) depends on ethnicity. CYP2C19 polymorphisms that produce poor metabolizers are found with frequencies of 2% to 5% in Caucasians, 4% in African Americans, 13% to 23% in Asians, and 38% to 79% in Polynesians and Micronesians.

 

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

CYP2C19 Allele

Nucleotide Change

Effect on Enzyme Metabolism

*1

None (wild type)

Extensive metabolizer (normal)

*2

c.681G>A

No activity

*3

c.636G>A

No activity

*4

c.1A>G

No activity

*6

c.395G>A

No activity

*7

c.819+2T>A

No activity

*8

c.358T>C

Severely decreased activity (70%-90%)

*17

c.-806C>T

Enhanced activity

 

The impact of CYP2C19 genotype on drug metabolism depends on many factors including the specific genotype detected (and predicted phenotype), as well as the type of drug. The following is a partial listing of drugs known to affect CYP2C19 activity:

 

Drugs that undergo metabolism by CYP2C19:

-Anticoagulants: clopidogrel (Plavix)

-Anticonvulsants: mephenytoin, diazepam, phenytoin, primidone

-Antidepressants: amitriptyline, citalopram, S-citalopram, clomipramine

-Antineoplastics: cyclophosphamide

-Antiretrovirals: nelfinavir

-Proton pump inhibitors: lansoprazole, omeprazole, pantoprazole

-Miscellaneous drugs: progesterone, propranolol, R-warfarin (less active isomer), proguanil, diazepam

Coadministration may decrease the rate of elimination of other drugs metabolized by CYP2C19

 

Drugs known to increase CYP2C19 activity:

-Carbamazepine, prednisone, rifampin

Coadministration of these drugs increase synthesis of CYP2C19 and increase the rate of elimination of drugs metabolized by CYP2C19

 

Drugs known to decrease CYP2C19 activity:

-Chloramphenicol, cimetidine, felbamate, fluoxetine, fluvoxamine, indomethacin, ketoconazole, lansoprazole, modafinil, omeprazole, probenecid, ticlopidine, topiramate

Coadministration will decrease the rate of metabolism of CYP2C19 metabolized drugs, increasing the possibility of toxicity, particularly in heterozygous individuals

 

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

Useful For Suggests clinical disorders or settings where the test may be helpful

Identifying patients who may be at risk for altered metabolism of drugs that are modified by CYP2C19

 

Predicting anticoagulation response to clopidogrel

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

 

CYP2C19 genotypes that lead to inactive or severely reduced activity alleles include *2, *3, *4, *6, *7, and *8 (see table in Clinical Information). If one of the listed variants is not identified, the genotype is designated as *1/*1, and the individual is most likely an extensive (normal) metabolizer. An individual who is heterozygous for an inactive or reduced activity allele is considered an intermediate metabolizer. An individual who is either homozygous or compound heterozygous for an inactive or reduced activity polymorphism is considered a poor metabolizer.

 

Individuals with the CYP2C19*17 variant (in the absence of any inactive or reduced activity polymorphisms) may have enhanced metabolism of drugs. If inactive or reduced activity polymorphisms and the *17 polymorphism are detected together, a range of potential phenotypes is given when warranted.

 

Drug-drug interactions and drug-metabolite inhibition must be considered when dealing with heterozygous individuals. Drug-metabolite inhibition can occur, resulting in inhibition of residual functional CYP2C19 catalytic activity.

 

Patients may also develop toxicity problems if liver and kidney functions are impaired.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Patients who 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. 

 

CYP2C19 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient’s CYP2C19 status.

 

Direct DNA testing will not detect all the known mutations that result in altered CYP2C19 activity. 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 is designed to detect only the polymorphisms specified above. Additional findings, such as small insertions and deletions or novel variants, will be reported if found. Other polymorphisms in the primer binding regions can affect the testing and, ultimately, the genotyping assessments made.

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.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Blaisdell J, Mohrenweiser H, Jackson J, et al: Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics 2002 Dec;12(9):703-711

2. Jeppesen U, Gram LF, Vistisen K, et al: Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996;51(1):73-78

3. Simon T, Verstuyft C, Mary-Krause M, et al: Genetic determinants response to clopidogrel and cardiovascular events. N Engl J Med 2009;360(4):363-375

4. Mega J, Close S, Wiviott D, et al: Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362


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