Selective CYP2C9 Inhibitors
Sulfamethoxazole is a selective inhibitor of CYP2C9, while other compounds like amiodarone and fluconazole also demonstrate significant CYP2C9 inhibition, though with less selectivity. 1
Selective CYP2C9 Inhibitors
Primary Selective Inhibitor
- Sulfamethoxazole: Research demonstrates that sulfamethoxazole selectively inhibits CYP2C9-mediated tolbutamide hydroxylation with an apparent Ki value of 271 μM 1
- This makes it a useful tool for in vitro studies requiring selective CYP2C9 inhibition
Other Notable CYP2C9 Inhibitors (Less Selective)
- Sulfaphenazole: Used as a positive control in CYP2C9 inhibition studies 2
- Amiodarone: Inhibits CYP2C9 (moderate inhibition) along with CYP2D6 and CYP3A4 3
- Fluconazole: Inhibits CYP2C9 but also affects other CYP enzymes
Clinical Significance of CYP2C9 Inhibition
Important Drug Classes Metabolized by CYP2C9
- Anticoagulants: Warfarin (S-isomer) 4
- NSAIDs: Ibuprofen, flurbiprofen, celecoxib 5
- Antidiabetics: Tolbutamide, glyburide 4
- Antiepileptics: Phenytoin 4
Potential Drug-Drug Interactions
- CYP2C9 inhibitors can increase plasma concentrations of drugs metabolized by this enzyme
- For example, propafenone inhibits CYP2C9, leading to increased warfarin concentrations (↑INR by 25%) 3
- When administering CYP2C9 inhibitors with drugs like phenytoin, monitor for excessive phenytoin effects 6
Mechanism of CYP2C9 Inhibition
Types of Inhibition
- Competitive inhibition: Most common mechanism
- Noncompetitive inhibition: Observed with certain compounds like Rhodiola rosea extract 2
- Mechanism-based inhibition: Seen with compounds like tienilic acid and suprofen 4
Structural Determinants of Inhibition
- CYP2C9 has multiple binding regions within its active site
- Key residues involved in ligand binding include Arg97, Phe110, Val113, Phe114, and others 4
- This complex binding site explains why different inhibitors may show varying potency depending on the substrate used for testing 7
Clinical Considerations
Pharmacogenetic Implications
- CYP2C9 genetic polymorphisms (e.g., CYP2C9*3) can influence the extent of drug-drug interactions
- Inhibition potency may differ between CYP2C9.1 (wild-type) and variant proteins like CYP2C9.3 7
- Patients with reduced-function CYP2C9 variants may experience more pronounced effects from CYP2C9 inhibitors
Monitoring Recommendations
- When using selective CYP2C9 inhibitors with narrow therapeutic index drugs:
Practical Applications
- In research settings, sulfamethoxazole can be used as a selective CYP2C9 inhibitor for in vitro drug metabolism studies
- In clinical practice, awareness of selective CYP2C9 inhibitors helps predict and prevent adverse drug interactions
- When prescribing medications known to be CYP2C9 substrates, consider checking for concomitant use of CYP2C9 inhibitors
Understanding selective CYP2C9 inhibitors is crucial for predicting drug interactions and optimizing pharmacotherapy, especially for drugs with narrow therapeutic indices like warfarin and phenytoin.