What Drugs Are Metabolized by CYP2C9? A Comprehensive Guide

October 13, 2025 •

4 min read

The human cytochrome P450 enzyme CYP2C9 is responsible for the metabolism of approximately 15-20% of all clinically used drugs that undergo phase I metabolism [1.8.6, 1.8.2]. Understanding what drugs are metabolized by CYP2C9 is critical for safe and effective pharmacotherapy.

Quick Summary

A detailed overview of the cytochrome P450 enzyme CYP2C9, listing the specific drugs it metabolizes (substrates), as well as common inhibitors and inducers. The clinical and genetic implications are also explored.

Key Points

Key Enzyme: CYP2C9 metabolizes 15-20% of clinically used drugs, including many with a narrow therapeutic index [1.8.2, 1.8.6].
Major Substrates: Common drug classes metabolized by CYP2C9 include NSAIDs (ibuprofen, naproxen), anticoagulants (warfarin), antiepileptics (phenytoin), and sulfonylureas (glipizide) [1.2.6].
Drug Interactions: CYP2C9 activity can be blocked by inhibitors (e.g., fluconazole, amiodarone) or increased by inducers (e.g., rifampin), leading to toxicity or treatment failure, respectively [1.8.4].
Genetic Variants: Polymorphisms like CYP2C9*2 and CYP2C9*3 create poor or intermediate metabolizers, who are at a higher risk of adverse drug reactions from standard doses [1.4.5, 1.5.6].
Clinical Significance: Understanding a patient's CYP2C9 status is critical for personalizing doses of drugs like warfarin and phenytoin to prevent serious adverse events like bleeding or neurotoxicity [1.4.3, 1.7.1].
Warfarin Metabolism: CYP2C9 is the primary enzyme that metabolizes the active S-enantiomer of warfarin, making it a crucial factor in anticoagulation therapy [1.8.6].
NSAID Risks: Poor metabolizers of CYP2C9 have reduced clearance of NSAIDs like ibuprofen and celecoxib, increasing the risk of adverse effects such as gastrointestinal bleeding [1.7.2, 1.5.3].

The Role of Cytochrome P450 2C9 in Drug Metabolism

The cytochrome P450 (CYP) family of enzymes is essential for breaking down (metabolizing) a vast number of substances, including a high percentage of therapeutic drugs [1.4.2]. Among these, CYP2C9 is one of the most abundant and clinically significant enzymes found in the liver, accounting for about 20% of the total CYP content [1.4.2, 1.2.7]. Its primary function is to carry out oxidative metabolism, a chemical process that typically converts drugs into more water-soluble compounds that are easier for the body to excrete [1.8.6].

This metabolic pathway is crucial for determining a drug's concentration in the body and the duration of its effect. The efficiency of CYP2C9 can vary significantly among individuals due to genetic differences, co-administered drugs, and other non-genetic factors [1.8.2]. This variability is particularly important for drugs with a narrow therapeutic index, where small changes in plasma concentration can lead to toxicity or loss of efficacy [1.8.6, 1.4.5]. Key examples of such drugs include the anticoagulant warfarin, the anti-epileptic phenytoin, and various oral hypoglycemic agents [1.8.4, 1.8.6].

Common Drugs Metabolized by CYP2C9 (Substrates)

CYP2C9 substrates are the drugs that the enzyme acts upon. Many common medications rely on CYP2C9 for their clearance from the body. These can be grouped into several major therapeutic classes [1.2.6].

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): CYP2C9 is the primary enzyme responsible for metabolizing many widely used NSAIDs [1.2.3]. This includes celecoxib, diclofenac, ibuprofen, naproxen, meloxicam, and piroxicam [1.2.1, 1.2.5].
Anticoagulants: The enzyme plays a critical role in the metabolism of the more potent (S)-enantiomer of warfarin, making it a key determinant of the drug's anticoagulant effect and dosage requirements [1.8.6, 1.6.3]. Other coumarin anticoagulants like acenocoumarol are also primarily metabolized by CYP2C9 [1.2.6].
Oral Hypoglycemic Agents (Sulfonylureas): Several drugs used to treat type 2 diabetes are CYP2C9 substrates, including glipizide, glimepiride, and tolbutamide [1.2.1, 1.2.6]. Inefficient metabolism can increase the risk of hypoglycemia [1.8.6].
Angiotensin II Receptor Blockers (ARBs): This class of antihypertensives includes losartan and irbesartan. CYP2C9 is responsible for converting losartan to its more potent active metabolite, E-3174 [1.2.1, 1.8.6].
Antiepileptics: Phenytoin is a well-known CYP2C9 substrate with a narrow therapeutic window. Decreased metabolism can quickly lead to toxicity [1.2.2, 1.8.6].
Other Notable Substrates: Other drugs metabolized by CYP2C9 include the statin fluvastatin and the diuretic torsemide [1.2.1, 1.2.6].

CYP2C9 Inhibitors and Inducers

Drug-drug interactions involving CYP2C9 are common and clinically significant. These interactions occur when one drug alters the metabolic activity of the CYP2C9 enzyme, affecting the plasma concentration of another drug (the substrate).

CYP2C9 Inhibitors are substances that block or decrease the enzyme's activity. This leads to slower metabolism of substrates, causing their levels in the blood to rise. This can increase the risk of dose-related toxicity and adverse effects [1.8.4].

Potent Inhibitors: Fluconazole (an antifungal) is a well-known strong inhibitor [1.3.5]. Amiodarone (an antiarrhythmic) and sulfamethoxazole (an antibiotic) are also significant inhibitors [1.2.3, 1.3.7].

CYP2C9 Inducers are substances that increase the enzyme's activity. This accelerates the metabolism of substrates, causing their levels in the blood to fall more rapidly. This can lead to a loss of therapeutic effect [1.8.4, 1.7.6].

Potent Inducers: Rifampin (an antibiotic) is a powerful inducer of CYP2C9, often doubling the clearance of its substrates [1.3.2, 1.3.7]. Other inducers include carbamazepine and phenobarbital [1.3.5].

Comparison of CYP2C9 Interactions


Category	Examples	Mechanism of Action	Clinical Implication on Substrates (e.g., Warfarin)
Substrates	Warfarin, Phenytoin, Ibuprofen, Losartan, Glipizide [1.2.1, 1.2.2]	Drugs that are broken down by the CYP2C9 enzyme.	Standard dose effectiveness is dependent on normal enzyme function.
Inhibitors	Fluconazole, Amiodarone, Sulfamethoxazole [1.2.3, 1.3.7]	Block or decrease CYP2C9 enzyme activity.	Slower metabolism, increased drug levels, and higher risk of toxicity (e.g., increased bleeding risk with warfarin) [1.8.4].
Inducers	Rifampin, Carbamazepine, Phenobarbital [1.3.2, 1.3.5]	Increase CYP2C9 enzyme synthesis and activity.	Faster metabolism, decreased drug levels, and potential loss of efficacy (e.g., reduced anticoagulant effect of warfarin) [1.7.6].

Pharmacogenomics: The Impact of Genetic Variants

Substantial inter-individual variability in CYP2C9 activity is attributed to genetic polymorphisms—common variations in the CYP2C9 gene [1.8.2]. These variants can lead to the production of an enzyme with reduced or no function, directly impacting how a person metabolizes certain drugs [1.4.5, 1.7.3].

Individuals can be classified into different metabolizer phenotypes based on their genetic makeup [1.5.2, 1.5.4]:

Normal Metabolizers (EMs): Carry two copies of the normal-function allele (*1). They metabolize drugs as expected.
Intermediate Metabolizers (IMs): Carry one normal-function allele and one reduced-function allele. They metabolize drugs slower than normal metabolizers [1.5.1].
Poor Metabolizers (PMs): Carry two reduced-function or no-function alleles. They metabolize drugs very slowly, which can lead to high drug concentrations from standard doses and an increased risk of adverse effects [1.5.1, 1.5.3].

The most studied variants are CYP2C9*2 and CYP2C9*3, which are most common in Caucasian populations and result in decreased enzyme activity [1.4.1, 1.8.5]. For example, patients with these variants require significantly lower doses of warfarin to achieve a therapeutic effect and have a higher risk of bleeding complications [1.6.3, 1.7.1]. Similarly, poor metabolizers taking standard doses of phenytoin or certain NSAIDs are at a higher risk for toxicity or adverse events like gastrointestinal bleeding [1.5.5, 1.7.2]. Other variants, such as CYP2C9*5, *6, *8, and *11, are more common in individuals of African ancestry and also lead to decreased metabolism [1.4.1].

Conclusion

CYP2C9 is a cornerstone of drug metabolism, responsible for processing a significant number of common medications. The interplay between substrates, inhibitors, inducers, and an individual's unique genetic makeup creates a complex clinical picture. Understanding what drugs are metabolized by CYP2C9 allows healthcare providers to anticipate potential drug-drug interactions, interpret adverse reactions, and personalize drug therapy—especially for high-risk medications with narrow therapeutic windows. The growing field of pharmacogenomics continues to refine this understanding, paving the way for genotype-guided dosing to improve both the safety and efficacy of many critical treatments.

For more in-depth information on CYP2C9 and its genetic variants, an authoritative resource is the Pharmacogenomics Knowledgebase (PharmGKB). [1.3.4]

Frequently Asked Questions

CYP2C9 is a crucial enzyme in the liver, belonging to the cytochrome P450 family. It is responsible for breaking down (metabolizing) about 15-20% of all prescription drugs, playing a major role in how the body processes medications like warfarin, phenytoin, and many NSAIDs [1.8.2, 1.8.6].

A CYP2C9 poor metabolizer has very little enzyme activity due to their genetic makeup. They break down certain medications very slowly, which can cause the drugs to build up in the body to toxic levels. This increases the risk of serious side effects from standard doses [1.5.1, 1.5.3].

Many common over-the-counter and prescription non-steroidal anti-inflammatory drugs (NSAIDs) are metabolized by CYP2C9. These include ibuprofen, naproxen, celecoxib, diclofenac, and meloxicam [1.2.1, 1.2.5].

CYP2C9 is the primary enzyme that metabolizes the active form of warfarin. Individuals with reduced CYP2C9 activity (poor or intermediate metabolizers) clear the drug more slowly, leading to an increased anticoagulant effect and a higher risk of bleeding. These patients typically require a lower dose of warfarin [1.6.3, 1.4.1].

A CYP2C9 inhibitor is a drug or substance that blocks the activity of the CYP2C9 enzyme. When taken with a drug that is a CYP2C9 substrate, the inhibitor can cause the substrate's concentration to increase, leading to a higher risk of toxicity. Examples include fluconazole and amiodarone [1.8.4, 1.3.7].

A CYP2C9 inducer is a drug that increases the production or activity of the CYP2C9 enzyme. This speeds up the metabolism of CYP2C9 substrates, reducing their effectiveness. Rifampin is a well-known inducer that can significantly lower the concentration of drugs like warfarin [1.3.2, 1.7.6].

Genetic testing for CYP2C9 can identify individuals who are intermediate or poor metabolizers. This information is particularly valuable before starting therapy with narrow-therapeutic-index drugs like warfarin or phenytoin, as it helps clinicians choose a safer starting dose and reduce the risk of adverse reactions [1.4.3, 1.8.2].