Sorted By Test Name - Mayo Medical Laboratories

2D6
83180
for adverse drug reactions involving fluoxetine(1) Assessing hypoglycemia with accepted dosing of oral
hypoglycemic agents and sulfonylureas(2) Assessing causes of idiosyncratic reactions to nonsteroidal
anti-inflammatory drugs(3) As an aid in altering dosing of antiepileptic drugs(4)
Interpretation: An interpretive report will be provided. Drug-drug interactions and drug-metabolite
inhibition must be considered when dealing with heterozygous individuals and individual homozygous for
the *2 allele. Drug-metabolite inhibition can occur, resulting in inhibition of residual functional CYP2C9
catalytic activity. Patients may also develop toxicity problems if liver and kidney function are impaired.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Llerena A, Dorado P, Berecz R, et al: Effect of CYP2D6 and CYP2C9
genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions. Eur J
Clin Pharmacol 2004;59:869-873 2. Niemi M, Cascorbi I, Timm R, et al: Glyburide and glimepiride
pharmacokinetics in subjects with different CYP2C9 genotypes Clin Pharmacol Ther 2002;72:326-332 3.
Martinez C, Blanco G, Ladero JM, et al: Genetic predisposition to acute gastrointestinal bleeding after
NSAIDs use. Br J Pharmacol 2004;141:205-208 4. Gage BF, Eby C, Milligan PE, et al: Use of
pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemostasis
2004;91:87-94 5. Hung CC, Lin CJ, Chen CC, et al: Dosage recommendation of phenytoin for patients
with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther Drug Monit 2004;26:534-540
Cytochrome P450 2D6 Genotype
Clinical Information: 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: 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
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