Sorted By Test Name - Mayo Medical Laboratories

subunit-1 (VKORC1), a small transmembrane protein of the endoplasmic reticulum that is part of the
vitamin K cycle and the target of warfarin therapy.(1) VKORC1 is primarily transcribed in the liver,
although it is present in smaller amounts in the heart and pancreas. Vitamin K epoxide, a by-product of
the carboxylation of blood coagulation factors, is reduced to vitamin K by VKORC1. A polymorphism
within the promoter of VKORC1 decreases expression of the gene, decreasing the availability of vitamin
K. This may cause increases in serum warfarin and overmedicating, driving INR above the therapeutic
target level. Thus, in both situations (polymorphisms in either CYP2C9 or VKORC1), a reduced warfarin
dose is needed to compensate for the effects of the polymorphism in order to maintain the target INR.
CYP2C9 CYP2C9 metabolizes a wide variety of drugs including warfarin and many nonsteroidal
anti-inflammatory drugs. It is also partially responsible for metabolizing other drugs such as fluoxetine,
fluvastatin, phenytoin, and oral hypoglycemic drugs. A number of specific polymorphisms have been
found in the CYP2C9 gene that result in enzymatic deficiencies. The following information outlines the
relationship between the polymorphisms detected in this assay and the effect on the activity of the enzyme
encoded by that allele: CYP2C9 Allele Nucleotide Change Effect on Enzyme Metabolism *1 None (wild
type) Extensive metabolizer (normal) *2 430C->T Reduced activity *3 1075A->C Minimal activity *4
1076T->C Reduced activity *5 1080C->G Reduced activity *6 818delA No activity Dosing of warfarin,
which is metabolized through CYP2C9, may require adjustment for the individual patient. Patients who
are poor metabolizers (reduced activity) may benefit by dose reductions or by being switched to other
comparable drugs that are not metabolized primarily by CYP2C9. The following is a partial listing of
drugs known to affect CYP2C9 activity as of the date of this report. A more complete listing is presented
in the drug label, available at URL:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf Drugs that undergo
metabolism by CYP2C9: -Angiotensin II blockers: irbesartan, losartan -Anticoagulants: warfarin (more
active S-isomer) -Antidepressants: amitriptyline (minor), fluoxetine -Nonsteroidal anti-inflammatory
drugs (NSAIDS): celecoxib, diclofenac, ibuprofen, naproxen, piroxicam, suprofen -Oral hypoglycemic
agents: glipizide, glimepiride, glyburide/glibenclamide, nateglinide, tolbutamide -Miscellaneous drugs:
fluvastatin, phenytoin, sulfamethoxazole, tamoxifen, torsemide -Coadministration of these drugs may
decrease the rate of elimination of other drugs metabolized by CYP2C9 Drugs known to increase
CYP2C9 activity: -Phenobarbital, rifampin, secobarbital -Coadministration of these drugs increase the
synthesis of CYP2C9, resulting in increased CYP2C9 activity and metabolism of warfarin. A dose
increase may be needed to maintain the INR in the target range Drugs known to decrease CYP2C9
activity: -Amiodarone, fenofibrate, fluconazole, fluvastatin, isoniazid, lovastatin, phenylbutazone,
sertraline, sulfamethoxazole, sulfaphenazole, teniposide, ticlopidine, voriconazole, zafirlukast
-Coadministration of these drugs may decrease the rate of metabolism of CYP2C9-metabolized drugs,
including warfarin, increasing the possibility of toxicity VKORC1 The -1639 promoter polymorphism is
located in the second nucleotide of an E-Box (CANNTG) and its presence disrupts the consensus
sequence, reducing promoter activity. In vitro experiments show a 44% higher transcription level of the G
versus the A allele.(1) The -1639 G->A nucleotide change results in decreased gene expression and
reduced enzyme activity.
Useful For: Identifying patients who may require warfarin dosing adjustments(2,3) including: -Patients
who have previously been prescribed warfarin and have required multiple dosing adjustments to maintain
the international normalized ratio in the target range -Patients with a history of thrombosis or bleeding
when previously taking warfarin -Patients being started on a first prescription for warfarin
Interpretation: An interpretive report will be provided. The normal genotype (wild-type) for CYP2C9
is termed CYP2C9*1. Other genotypes that lead to inactive or reduced activity alleles include CYP2C9*2,
CYP2C9*3, CYP2C9*4, CYP2C9*5, and CYP2C9*6. An individual who has homozygous wild-type,
CYP2C9*1/CYP2C9*1, is considered an extensive metabolizer. The normal genotype for VKORC1 is
-1639G. A polymorphism at -1639A reduces VKORC1 expression. The VKORC1 GA or AA genotype
leads to a significant decrease in mRNA expression in the liver compared with individuals with the GG
genotype. Individuals who have polymorphisms in both the VKORC1 promoter (GA or AA) and also in
CYP2C9 should receive a reduced dose of warfarin to maintain the international normalized ratio in the
target range; dosing adjustments are required when polymorphisms in both genes are present. 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 CYP2C9
or VKORC1 catalytic activity. A clinical pharmacologist should be consulted for assessing the potential
for drug interactions. Patients may also develop toxicity problems if liver and kidney function are
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