What substances interfere with CYP2C9?

Substances that Interfere with CYP2C9

Substances that inhibit CYP2C9 include sulfonamides (sulfamethoxazole), metronidazole, fluconazole, voriconazole, amiodarone, and certain NSAIDs, while substances that induce CYP2C9 include rifampin, phenobarbital, carbamazepine, and nafcillin. 1

CYP2C9 Inhibitors

CYP2C9 is one of the most important drug-metabolizing enzymes in the human liver, responsible for metabolizing approximately 15-20% of clinically used drugs 2, 3. Inhibition of this enzyme can lead to increased plasma concentrations of CYP2C9 substrates and potential toxicity.

Strong CYP2C9 Inhibitors:

• Antimicrobials:

  • Sulfonamides (particularly sulfamethoxazole) 1
  • Metronidazole 1
  • Fluconazole 1
  • Voriconazole 1

• Cardiovascular drugs:

  • Amiodarone 1, 4

• Other inhibitors:

  • Phenylbutazone 4
  • Sulfinpyrazone 4
  • Sulfaphenazole 4

Clinical Significance of CYP2C9 Inhibition

When CYP2C9 inhibitors are co-administered with CYP2C9 substrates like warfarin, significant increases in drug concentrations can occur. For example:

• Co-administration of sulfamethoxazole with warfarin nearly doubles the risk of serious bleeding 1
• Pre-emptive warfarin dose reductions of 25% for sulfamethoxazole and 33% for metronidazole are recommended 1, 5

CYP2C9 Inducers

Induction of CYP2C9 can lead to decreased plasma concentrations of CYP2C9 substrates and potential therapeutic failure.

CYP2C9 Inducers:

• Rifampin 1, 4
• Phenobarbital 1, 4
• Carbamazepine 1, 4
• Dexamethasone 2
• Nafcillin 1
• Other anti-staphylococcal penicillins (flucloxacillin, cloxacillin) 1

Clinical Significance of CYP2C9 Induction

When CYP2C9 inducers are co-administered with CYP2C9 substrates:

• Higher maintenance doses of the substrate may be required
• The full induction effect may take 2-4 weeks to develop
• Effects may persist for 2-4 weeks after discontinuation of the inducer 1

Common CYP2C9 Substrates

Understanding which drugs are metabolized by CYP2C9 is important for predicting potential drug interactions:

• Anticoagulants: S-warfarin 6, 3
• Antidiabetics: Tolbutamide, glyburide 2, 3
• NSAIDs: Diclofenac, celecoxib 2, 3
• Antihypertensives: Losartan 2, 3
• Anticonvulsants: Phenytoin 2, 3
• Diuretics: Torasemide 2

Genetic Polymorphisms and CYP2C9 Activity

Genetic variations in the CYP2C9 gene can significantly affect enzyme activity:

• CYP2C92 and CYP2C93 are the most common variants with reduced enzymatic activity 6, 3
• Individuals homozygous for CYP2C9*3 have markedly diminished metabolic capacity for most CYP2C9 substrates 4
• These genetic variations can further compound the effects of drug interactions with CYP2C9 inhibitors or inducers 3, 7

Clinical Recommendations

1. When prescribing CYP2C9 substrates:

   • Screen for concurrent use of CYP2C9 inhibitors or inducers
   • Consider dose adjustments when adding or removing interacting medications
   • Monitor more frequently when initiating or discontinuing interacting medications 5

2. For warfarin specifically:

   • Reduce warfarin dose by 25% when adding sulfamethoxazole
   • Reduce warfarin dose by 33% when adding metronidazole
   • Monitor INR within 2-3 days of starting any new medication 1, 5

3. Timing considerations:

   • The order of drug initiation matters - adding an inhibitor to stable warfarin therapy is more likely to cause toxicity than starting both medications simultaneously 1
   • Effects of inducers may take weeks to fully develop or resolve 1

Understanding these interactions is crucial for safe medication management and preventing adverse drug reactions that could lead to increased morbidity and mortality.