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WRF
8760
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: -Phenobarbitol, 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
impaired.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Oldenburg J, Bevens C, Muller C, Watzka M: Vitamin K epoxide reductase
complex subunit I (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal
2006;8(3-4):347-353 2. Yuan H, Chen J, Lee M, et al: A novel functional VKORC1 promoter
polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum
Mol Genet 2005;14:1745-1751 3. Sconce E, Khan T, Wynne H, et al: The impact of CYP2C9 and
VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements proposal for
a new dosing regimen. Blood 2005;106:2329-2333
Warfarin, Serum
Clinical Information: Warfarin (Coumadin) is an anticoagulant that acts by antagonizing the action
of vitamin K resulting in the same coagulation abnormalities produced by vitamin K deficiency. Warfarin
reduces the levels of prothrombin and factors VII, IX, and X, thereby prolonging the prothrombin and
partial thromboplastin times. Warfarin produces its anticoagulant effect within 36 to 72 hours of initiating
therapy, and the duration of action may persist for 4 to 5 days following withdrawal of drug. Warfarin
circulates almost completely bound to albumin (>98%), and its half-life ranges from 20 to 60 hours.
Abnormal bleeding is the chief complication of overdose.
Useful For: Monitoring patients whose prothrombin time is inconsistent with the prescribed warfarin
dose, particularly when failure to comply or surreptitious drug use is suspected. Note: This test is not
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