Comprehensive List of CYP450 Inhibitors
The most clinically significant CYP450 inhibitors include proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole), macrolide antibiotics (erythromycin, clarithromycin), azole antifungals, HIV protease inhibitors, and certain antidepressants. 1
Major CYP450 Inhibitors by Isoenzyme
CYP1A2 Inhibitors
- Fluvoxamine (strong)
- Ciprofloxacin
- Enoxacin
- Cimetidine
- Oral contraceptives
- Caffeine
CYP2C9 Inhibitors
- Fluconazole
- Amiodarone
- Sulfamethoxazole
- Cimetidine
- Metronidazole
- Fluoxetine
CYP2C19 Inhibitors
- Omeprazole and other PPIs
- Fluconazole
- Fluvoxamine
- Cimetidine
- Fluoxetine
- Ticlopidine
- Esomeprazole
CYP2D6 Inhibitors
- Fluoxetine and norfluoxetine
- Paroxetine
- Quinidine
- Duloxetine
- Bupropion and hydroxybupropion
- Terbinafine
- Cinacalcet
- Sertraline (moderate)
CYP3A4 Inhibitors
- Ritonavir (most potent)
- Indinavir, nelfinavir, amprenavir (moderate)
- Saquinavir (less potent)
- Ketoconazole
- Itraconazole
- Erythromycin
- Clarithromycin
- Diltiazem and desmethyldiltiazem
- Verapamil
- Fluconazole
- Grapefruit juice
- Aprepitant
- Cyclosporine
Clinical Significance of CYP450 Inhibition
CYP450 inhibition is a principal mechanism for metabolism-based drug-drug interactions 2. When a CYP450 inhibitor is administered with a medication metabolized by the same enzyme, the plasma concentration of the substrate drug can increase, potentially leading to:
- Increased therapeutic effects
- Increased risk of adverse effects
- Toxicity with narrow therapeutic index drugs
Examples of Clinically Significant Interactions
PPIs and clopidogrel: PPIs (especially omeprazole) inhibit CYP2C19, which is necessary for converting clopidogrel to its active metabolite, potentially reducing its antiplatelet effect 1
Macrolides and certain medications: Erythromycin and clarithromycin inhibit CYP3A4, leading to increased concentrations of drugs like astemizole, cisapride, terfenadine, and benzodiazepines 1
HIV protease inhibitors and various drugs: Ritonavir is a potent CYP3A4 inhibitor that can dramatically increase concentrations of drugs metabolized by this enzyme 1
Antidepressants and tricyclic antidepressants: SSRIs like fluoxetine inhibit CYP2D6, increasing plasma concentrations of tricyclic antidepressants 3
Special Considerations
Genetic Polymorphisms
Individual variations in CYP450 enzymes (particularly CYP2C19 and CYP2D6) can lead to different drug metabolism rates. Patients can be classified as:
- Poor metabolizers
- Intermediate metabolizers
- Extensive (normal) metabolizers
- Ultra-rapid metabolizers 4
Metabolites as Inhibitors
Some drug metabolites can also inhibit CYP450 enzymes, sometimes more potently than the parent drug:
- Norfluoxetine (metabolite of fluoxetine)
- Hydroxyitraconazole (metabolite of itraconazole)
- Desmethyldiltiazem (metabolite of diltiazem)
- Desethylamiodarone (metabolite of amiodarone) 5
Organ Transplant Considerations
All azoles inhibit CYP3A4, which metabolizes common antirejection medications including cyclosporine, tacrolimus, and sirolimus. This interaction requires careful monitoring and dose adjustment of immunosuppressants 1.
Practical Management Strategies
Recognize high-risk combinations: Be particularly vigilant with narrow therapeutic index drugs
Consider alternative medications: When possible, choose drugs metabolized by different CYP450 enzymes
Adjust dosages: Reduce substrate drug doses when administered with potent inhibitors
Monitor drug levels: For drugs with narrow therapeutic indices, consider therapeutic drug monitoring
Be aware of genetic factors: Consider that genetic polymorphisms may compound the effects of drug inhibition
By understanding the pattern of CYP450 inhibition, clinicians can predict and prevent potentially harmful drug interactions, especially in patients on multiple medications.