What medications are metabolized by CYP 3A4 (Cytochrome P450 3A4)?

Medications Metabolized by CYP3A4

CYP3A4 metabolizes approximately 30-50% of all currently available medications, including statins (simvastatin, lovastatin, atorvastatin), benzodiazepines (alprazolam, triazolam, midazolam), immunosuppressants (cyclosporine, tacrolimus), and many other drug classes. 1

Major Drug Classes Metabolized by CYP3A4

Immunosuppressants

• Calcineurin Inhibitors:
  • Cyclosporine (CsA) - extensively metabolized by CYP3A4 2
  • Tacrolimus - extensively metabolized by hepatic and intestinal CYP3A4 2
• mTOR Inhibitors:
  • Sirolimus
  • Everolimus

Statins

• CYP3A4-dependent statins:
  • Simvastatin - administered as inactive lactone prodrug, avidly metabolized by CYP3A4 2
  • Lovastatin - administered as inactive lactone prodrug, avidly metabolized by CYP3A4 2
  • Atorvastatin - administered as active hydroxy-acid form, but still metabolized by CYP3A4 2
• Less CYP3A4-dependent statins:
  • Pravastatin - eliminated by multiple pathways, particularly glucuronidation 2
  • Fluvastatin - primarily uses CYP2C9 for metabolism 2
  • Rosuvastatin

Benzodiazepines

• Alprazolam - extensively metabolized by CYP3A4 3
• Triazolam
• Midazolam
• Diazepam (partially)
• Brotizolam 4

Anticonvulsants

• Carbamazepine - both substrate and potent inducer of CYP3A4 5

Anti-HIV Medications

• Protease inhibitors (ritonavir, saquinavir)
• Non-nucleoside reverse transcriptase inhibitors (delavirdine)

Antibiotics

• Macrolides (clarithromycin, erythromycin)

Calcium Channel Blockers

• Diltiazem
• Verapamil

Clinical Significance and Drug Interactions

Inhibitors of CYP3A4

When these are co-administered with CYP3A4 substrates, they can increase substrate drug levels:

• Azole antifungals (ketoconazole, itraconazole)
• Macrolide antibiotics (clarithromycin, erythromycin)
• Calcium channel blockers (diltiazem, verapamil)
• Grapefruit juice
• HIV protease inhibitors (ritonavir)
• Antidepressants (nefazodone, fluvoxamine) 6, 7

Inducers of CYP3A4

When these are co-administered with CYP3A4 substrates, they can decrease substrate drug levels:

• Rifampin
• Phenytoin
• Phenobarbital
• Carbamazepine
• St. John's Wort 8

Potential Consequences of CYP3A4 Interactions

Serious Adverse Effects

• Rhabdomyolysis: When CYP3A4 inhibitors are given with CYP3A4-metabolized statins 2
• Excessive sedation: When CYP3A4 inhibitors are given with benzodiazepines 6
• Transplant rejection: When CYP3A4 inducers decrease immunosuppressant levels 2
• Toxicity: When CYP3A4 inhibitors increase levels of narrow therapeutic index drugs 1

Management Strategies

• Dose adjustment: Reduce substrate dose when adding a CYP3A4 inhibitor 1
• Alternative medication selection: Choose drugs with different metabolic pathways
• Therapeutic drug monitoring: Especially for narrow therapeutic index drugs 1
• Avoidance of contraindicated combinations: For high-risk combinations 1

Practical Considerations

When prescribing medications metabolized by CYP3A4, clinicians should:

• Screen for potential drug interactions before prescribing
• Consider alternative medications with different metabolic pathways when possible
• Adjust doses appropriately when co-administration cannot be avoided
• Monitor for adverse effects and drug levels when appropriate
• Be aware that approximately one-third of patients on CYP3A4-metabolized statins are also prescribed concomitant CYP3A4 inhibitors 9

Understanding CYP3A4 metabolism is critical for preventing potentially dangerous drug interactions and optimizing therapeutic outcomes.