CYP2C9 is a cytochrome P450 enzyme responsible for metabolizing approximately 15% of clinically used drugs, including warfarin, many NSAIDs, and several oral hypoglycemic agents. The *2 variant (rs1799853) reduces enzyme activity by about 30%, affecting drug clearance and required dosing. This is one of the most clinically actionable pharmacogenetic variants, with established guidelines for drug dosing.
Understanding CYP2C9
CYP2C9 is a major drug-metabolizing enzyme:
- Location: Primarily in liver
- Function: Phase I drug metabolism (oxidation)
- Substrates: Approximately 100+ medications
- Clinical importance: High - affects many narrow therapeutic index drugs
The *2 Variant (Arg144Cys)
This variant changes an amino acid affecting enzyme activity:
- C allele (*1): Arginine at position 144 - normal activity
- T allele (*2): Cysteine at position 144 - reduced activity (~70% of normal)
Understanding Your Genotype
- *1/*1 (C/C): Normal metabolizer - standard drug metabolism
- *1/*2 (C/T): Intermediate metabolizer - moderately reduced activity
- *2/*2 (T/T): Poor metabolizer at this locus - significantly reduced activity
Combined with *3
CYP2C9 function depends on both *2 and *3 variants:
- *1/*1 = Normal metabolizer
- *1/*2 or *1/*3 = Intermediate metabolizer
- *2/*2, *2/*3, or *3/*3 = Poor metabolizer
Warfarin: The Primary Clinical Application
Why Warfarin Dosing Matters
- Warfarin has a narrow therapeutic index
- Too little = ineffective, risk of clots
- Too much = bleeding risk
- CYP2C9 metabolizes the more potent S-warfarin
Dosing Implications
| CYP2C9 Genotype | Metabolizer Status | Typical Dose Adjustment |
|---|---|---|
| *1/*1 | Normal | Standard dosing |
| *1/*2 | Intermediate | ~20% dose reduction |
| *2/*2 | Poor | ~40% dose reduction |
| *1/*3 | Intermediate | ~30% dose reduction |
| *2/*3 | Poor | ~50% dose reduction |
VKORC1 Interaction
- Warfarin also affected by VKORC1 genotype
- CYP2C9 + VKORC1 together explain ~50% of dose variability
- FDA-approved dosing algorithms incorporate both genes
Other Affected Medications
NSAIDs
- Ibuprofen: Slower clearance in poor metabolizers
- Diclofenac: Reduced metabolism
- Celecoxib: Higher levels with *2 or *3 variants
- Implications: Increased GI bleeding risk, longer duration of action
Sulfonylureas (Diabetes Medications)
- Glipizide, glyburide, glimepiride: CYP2C9 substrates
- Poor metabolizers: Higher drug levels, increased hypoglycemia risk
- Clinical action: May need lower doses or alternative medications
Losartan
- CYP2C9 converts losartan to active metabolite
- Poor metabolizers may have reduced efficacy (less active metabolite)
- Consider alternative ARBs not dependent on CYP2C9
Phenytoin
- Anti-epileptic with narrow therapeutic window
- CYP2C9 variants affect clearance
- Poor metabolizers at risk for toxicity
Clinical Guidelines
CPIC Guidelines
The Clinical Pharmacogenetics Implementation Consortium provides dosing guidance:
- Warfarin dosing algorithms available
- Phenytoin dose adjustments recommended
- Celecoxib dose reductions for poor metabolizers
- Guidelines updated regularly as evidence grows
FDA Drug Labels
- Warfarin label includes CYP2C9 pharmacogenetic information
- Several other drug labels mention CYP2C9
- Genotype information becoming standard in many labels
Drug-Drug Interactions
CYP2C9 Inhibitors
These drugs can further reduce CYP2C9 activity:
- Fluconazole (potent inhibitor)
- Amiodarone
- Fluvastatin
- Sulfamethoxazole
Combined Effect
- Genetic poor metabolizer + inhibitor = severe reduction in activity
- Extra caution needed with CYP2C9 substrate drugs
- Increased monitoring recommended
Endogenous Substrates
Arachidonic Acid Metabolism
- CYP2C9 converts arachidonic acid to EETs (epoxyeicosatrienoic acids)
- EETs have anti-inflammatory and vasodilatory effects
- *2 variant may affect endogenous EET production
- Possible cardiovascular implications
Vitamin D
- Some vitamin D metabolism involves CYP2C9
- Clinical significance less established
Prevalence
- *2 allele frequency: ~10-15% in Europeans
- Very rare: In East Asian and African populations
- *2/*2 genotype: ~1-2% of Europeans
- Population-specific: Testing most relevant for European ancestry
Testing Considerations
When to Test
- Before starting warfarin (recommended by many guidelines)
- Unexplained bleeding or difficulty achieving stable INR
- Before high-risk medications in poor metabolizers
- Family history of adverse drug reactions to CYP2C9 substrates
Testing Approach
- Both *2 and *3 should be tested together
- Preemptive testing increasingly common
- Results remain relevant for life
Testing with NutraHacker
NutraHacker's Complete Mutation Report analyzes CYP2C9 along with other pharmacogenetic variants, helping you understand how your genetics may affect drug metabolism.
Frequently Asked Questions
Should I avoid warfarin if I have the *2 variant?
No, you don't need to avoid warfarin, but your doctor should know your genotype. Warfarin is still effective and appropriate for many people with CYP2C9 variants - they just typically need lower doses. Dosing algorithms that incorporate genetics help determine the right starting dose. With appropriate dosing, warfarin can be used safely.
Does this affect over-the-counter pain medications?
CYP2C9 metabolizes some NSAIDs like ibuprofen and naproxen. If you're a poor metabolizer, these drugs may have longer effects and potentially higher GI bleeding risk with regular use. For occasional use, this is unlikely to be clinically significant, but for regular use, be aware of potential for accumulation and discuss with your healthcare provider.
Is pharmacogenetic testing covered by insurance?
Coverage varies by insurer and indication. Testing before warfarin initiation is often covered because evidence for cost-effectiveness is strong. Medicare covers pharmacogenetic testing for certain indications. Check with your insurer about specific coverage for your situation.
References
- Johnson JA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017;102(3):397-404.
- Lee CR, et al. CYP2C9 genotype as a predictor of drug disposition in humans. Methods Find Exp Clin Pharmacol. 2002;24(Suppl D):16-24.
- Rettie AE, et al. Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol. 2005;45:477-494.