Interpretive Handbook

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. Some individuals have altered CYP2C19 gene sequences that result in synthesis of enzyme devoid of catalytic activity or in enzyme with diminished catalytic activity. These individuals metabolize clopidogrel, mephenytoin, omeprazole, diazepam, proguanil, and propranolol poorly. A number of specific polymorphisms have been found in the CYP2C19 gene that result in enzymatic deficiencies. The frequency of these polymorphisms varies within the major ethnic groups. 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:

Individuals without inactivating polymorphisms have the phenotype of an extensive drug metabolizer and are designated as CYP2C19*1. All of the identified polymorphisms are autosomal recessive. Consequently, only individuals who are homozygous or who are 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.

Individuals receiving clopidogrel who are carriers (heterozygous) or homozygous for the CYP2C19 polymorphisms detected by this test will likely require a dose increase to achieve effective inhibition of platelet aggregation.

Dosing of drugs that are metabolized through CYP2C19 may require adjustment for the individual patient. Patients who are poor metabolizers may benefit by dose alteration or by being switched to other comparable drugs that are not metabolized primarily by CYP2C19. CYP2C19 poor metabolizers may fail to activate clopidogrel, a prodrug. Consideration of increased dosing or alternative anticoagulant is suggested.

The following is a partial listing of drugs known to affect CYP2C19 activity as of the date of this report.

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

Identifying patients who are poor metabolizers or extensive metabolizers of drugs that are modified by CYP2C19

Individuals who have resistance to anticoagulation with clopidogrel

An interpretive report will be provided.

The normal genotype for CYP2C19 is CYP2C19*1. Other genotypes that lead to inactive or reduced activity alleles include CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*6, CYP2C19*7, and CYP2C19*8. An individual who is homozygous wild type, or CYP2C19*1/CYP2C19*1, is considered an extensive metabolizer. An individual who is heterozygous for the wild type and variant genotype is considered an intermediate metabolizer. An individual who is either a homozygous variant or compound heterozygous variant genotype is considered a poor metabolizer. Individuals who are homozygous for *1 but who also have the CYP2C19*17 promoter polymorphism may have enhanced metabolism of drugs, and may require higher drug doses to maintain therapeutic effectiveness. Individuals with a *17 allele may activate prodrugs, such as clopidogrel, to the active metabolites to a greater extent than extensive metabolizers. 

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.

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

An interpretive report will be provided.

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, Loft S, 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