CYP2C9 is a member of the IIC subfamily of the cytochrome p450 genes, responsible for metabolizing numerous drugs, such as phenytoin, tamoxifen, warfarin, fluvastin, and many nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen. People who carry CYP2C9 variants may process such drugs differently.
SNPs in CYP2C9 include:
- rs1057910; two variants encode the CYP2C9*1 and CYP2C9*3 alleles
- rs1799853, versions of which encode CYP2C9*2 alleles
Plavix, the trade name for clopidogrel, is a drug commonly prescribed to reduce the chance of a type of heart disease (acute coronary syndrome), and it inhibits CYP2C9 at high enough doses. This may therefore interfere with the metabolism of drugs processed by CYP2C9, and individuals with CYP2C9 SNP variants that encode lower metabolizers to begin with would presumably be at greater risk for such side-effects when taking Plavix at the same time as drugs metabolized by CYP2C9.
A more detailed list of CYP2C9 SNPs includes:
In one of the largest "negative" studies reported to date, three independent studies totaling over 52,000 individuals found no association between CYP2C9 polymorphisms (specifically, the *2 and *3 alleles) and risk of subclinical atherosclerosis, ischemic vascular disease or death after ischemic heart disease.[PMID 19652664]
Excerpt from the FDA warfarin dosing guidelines:
In 2007, the FDA modified the warfarin label, stating that CYP2C9 and VKORC1 genotypes may be useful in determining the optimal initial dose of warfarin [Article:17906972]. The label was further updated in 2010 to include a table (Table 1) describing recommendations for initial dosing ranges for patients with different combinations of CYP2C9 and VKORC1 genotypes.
Genetics-based algorithms also better predict warfarin dose than the FDA-approved warfarin label table [Article:21272753]. Therefore, the use of pharmacogenetic algorithm-based dosing is recommended when possible, although if electronic means for such dosing are not available, the table-based dosing approaches (Table 1) are suggested. The range of doses by VKORC1 genotype and the range of dose recommendations/predictions by the FDA table and algorithm are shown in Figure 2.
Figure 2 Legend: Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype in 3,616 patients recruited by the International Warfarin Pharmacogenetics Consortium (IWPC) who did not carry the CYP2C9*2 or *3 allele (i.e., coded as *1*1 for US Food and Drug Administration (FDA) table and algorithm dosing). The range of doses within each genotype group recommended on the FDA table is shown via the shaded rectangle. The range of doses predicted using the IWPC dosing algorithm in these 3,616 patients is shown by the solid lines.
Figure 2 demonstrates that the range of individuals covered by the FDA table is much narrower than that of the algorithm. The article and supplement detail important variables that are not covered by the table that should also be taken into consideration.
Table 1: Recommended daily warfarin doses (mg/day) to achieve a therapeutic INR based on CYP2C9 and VKORC1 genotype using the warfarin product insert approved by the United States Food and Drug Administration:
VKORC1 Genotype (-1639G>A, rs9923231) CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3 GG 5-7 5-7 3-4 3-4 3-4 0.5-2 GA 5-7 3-4 3-4 3-4 0.5-2 0.5-2 AA 3-4 3-4 0.5-2 0.5-2 0.5-2 0.5-2 Reproduced from updated warfarin (Coumadin®) product label.
Supplemental Table S1. Genotypes that constitute the * alleles for CYP2C9
Allele Constituted by genotypes at: Amino acid changes Enzymatic Activity
- 1 reference allele at all positions Normal
- 2 C>T at rs1799853 R144C Decreased
- 3 A>C at rs1057910 I359L Decreased
08/16/2007 FDA approved updated labeling of Warfarin (marketed as Coumadin) http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm152972.htm
Audience: Hematologists, other healthcare providers, consumers
FDA approved updated labeling to include pharmacogenomics information to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for the widely used blood-thinning drug, Coumadin. This new information explains that people's genetic makeup may influence how they respond to the drug. Specifically, people with variations in two genes may need lower warfarin doses than people without these genetic variations. The two genes are called CYP2C9 and VKORC1. The CYP2C9 gene is involved in the breakdown (metabolism) of warfarin and the VKORC1 gene helps regulate the ability of warfarin to prevent blood from clotting.
The dosage and administration of warfarin must be individualized for each patient according to the particular patient's prothrombin time (PT) / International Normalized Ratio (INR) response to the drug. The specific dose recommendations are described in the warfarin product labeling, along with the new information regarding the impact of genetic information upon the initial dose and the response to warfarin. Ongoing warfarin therapy should be guided by continued INR monitoring.
[August 16, 2007 - Drug Information Page - FDA]