Sorted By Test Name - Mayo Medical Laboratories

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 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: CYP2C19 Allele Nucleotide Change Effect on Enzyme Metabolism *1 None (wild
type) Extensive metabolizer (normal) *2 681G->A No activity *3 636G->A No activity *4 1A->G No
activity *6 395G->A No activity *7 IVS5+2T->A No activity *8 358T->C Severely decreased activity
(70-90%) *17 c.-806C>T Enhanced Metabolizer 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 anticoagulants 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
-Antineoplastic drugs: 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.
Useful For: Identifying patients who are poor metabolizers or extensive metabolizers of drugs that are
modified by CYP2C19 Evaluating individuals who have resistance to anticoagulation with clopidogrel
Interpretation: 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 wildtype, or CYP2C19*1/CYP2C19*1, is considered an extensive metabolizer. An
individual who is heterozygous for the wildtype and variant genotype is considered an intermediate
metabolizer. Finally, 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 function are impaired.
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