Sorted By Test Name - Mayo Medical Laboratories

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: CYP2D6 Allele Nucleotide Change Effect on Enzyme
Metabolism *1 None (wild type) Extensive metabolism (normal) *2 2850C->T Decreased activity *2A
2850C->T and -1584C->G Increased activity *3 2549delA No activity *4 1846G->A No activity *5 Gene
deletion No activity *6 1707delT No activity *7 2935A->C No activity *8 1758G->T No activity *9
2613delAGA Decreased activity *10 100C->T Decreased activity *11 883G->C No activity *12
124G->A No activity *14A 100C->T and 1758G->A No activity *14B 1758G->A Decreased activity *15
138insT No activity *17 1023C->T Decreased activity Gene duplication Depends on the allele duplicated
(increased/no effect) 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.
Useful For: Identifying patients who are poor or extensive metabolizers of antidepressant drugs
metabolized by CYP2D6 Adjusting dosages for antidepressant drugs that are metabolized by CYP2D6
Interpretation: 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