Cytochrome P450 2C9 Genotype by Sequence Analysis, Blood
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Primary metabolism of many drugs is performed by cytochrome P450 (CYP450), a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP450 enzymes, 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, oral hypoglycemic drugs, and phenytoin.
CYP2C9-mediated drug metabolism is variable. Some individuals have altered CYP2C9 gene sequences that result in synthesis of enzyme devoid of catalytic activity or in enzyme with diminished catalytic activity. These individuals may metabolize various drugs at a slower rate than normal and may require dosing adjustments to prevent adverse drug reactions. However, CYP2C9 alleles with "reduced function" may metabolize different drugs at different rates, ranging from near normal to poor but the literature on this is incomplete at this time.
A number of specific polymorphisms have been found in the CYP2C9 gene that results in enzymatic deficiencies. The following information outlines the relationship between the polymorphisms detected in the assay and the effect on the enzyme activity encoded by that allele:
Effect on Enzyme Metabolism
None (wild type)
Extensive metabolizer (normal)
Individuals without inactivating polymorphisms have the phenotype of an extensive drug metabolizer and are designated as CYP2C9*1/*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. The CYP2C9*2 allele has greater residual activity than other alleles. Consequently, an individual homozygous for the *2 allele is predicted to be an intermediate metabolizer.
Dosing of drugs that are metabolized through CYP2C9 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 CYP2C9. The following is a partial listing of drugs known to affect CYP2C9 activity as of the date of this report.
Drugs that undergo metabolism primarily or in part by CYP2C9:
-Angiotensin II blockers: irbesartan, losartan
-Antidepressants: amitriptyline (minor), fluoxetine (minor)
-Nonsteroidal anti-inflammatory drugs (NSAIDS): celecoxib, diclofenac, ibuprofen, naproxen, piroxicam, suprofen
-Oral hypoglycemic agents: glipizide, glimepiride, glyburide/glibenclamide, nateglinide, tolbutamide
-Miscellaneous drugs: fluvastatin, phenytoin, rosuvastatin (minor), sulfamethoxazole, tamoxifen, torsemide
-Coadministration may decrease the rate of elimination of other drugs metabolized by CYP2C9.
Drugs known to increase CYP2C9 activity:
-Rifampin, secobarbital, phenobarbital
-Coadministration of these drugs increases the concentration of CYP2C9 and increases the elimination of drugs metabolized by CYP2C9.
Drugs known to decrease CYP2C9 activity:
-Amiodarone, fluconazole, fluvastatin, fluvoxamine, isoniazid, lovastatin, phenylbutazone, sertraline, sulfamethoxazole, sulfaphenazole, teniposide, ticlopidine, voriconazole, zafirlukast.
-Coadministration will decrease the rate of metabolism of CYP2C9-metabolized drugs, increasing the possibility of toxicity, particularly in heterozygous individuals.
Predicting metabolism status for drugs that are modified by CYP2C9
Evaluating patients for adverse drug reactions involving fluoxetine(1)
As an aid in altering dosing of antiepileptic drugs such as phenytoin(4)
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.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Direct DNA testing will not detect all the known mutations that result in decreased or inactive CYP2C9. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an intermediate or poor metabolizer phenotype.
This test detects only the specified polymorphisms. Additional findings, such as small insertions and deletions or novel mutations, will be reported if found. Other polymorphisms in the primer binding regions can affect the testing, and ultimately, the genotyping assessments made.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
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. 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