What are the strong CYP3A4 (cytochrome P450 3A4) or P-glycoprotein inhibitors or inducers?

Strong CYP3A4 and P-glycoprotein Inhibitors and Inducers

Strong CYP3A4 and P-glycoprotein inhibitors include azole antifungals (ketoconazole, itraconazole, voriconazole, posaconazole), HIV protease inhibitors (ritonavir, nelfinavir, saquinavir, indinavir, atazanavir), and clarithromycin, while strong inducers include rifampin, rifabutin, rifapentin, phenytoin, carbamazepine, phenobarbital, and St. John's wort. 1

Strong Dual CYP3A4 and P-glycoprotein Inhibitors

These agents inhibit both pathways simultaneously and cause the most clinically significant drug interactions:

Azole Antifungals

• Ketoconazole causes approximately 2.5-fold increase in drug exposure when combined with substrates like rivaroxaban 1
• Itraconazole is contraindicated with many CYP3A4/P-gp substrates due to profound increases in plasma concentrations 1
• Voriconazole and posaconazole share similar potent inhibitory effects 1

HIV Protease Inhibitors

• Ritonavir increases drug exposure by 2.5-fold for CYP3A4/P-gp substrates 1
• Nelfinavir, saquinavir, indinavir, and atazanavir all demonstrate strong dual inhibition 1
• These agents are contraindicated with rivaroxaban and require dose adjustments with apixaban 1

Macrolide Antibiotics

• Clarithromycin acts as a strong inhibitor of both pathways, increasing drug exposure 1.5-fold 1
• Telithromycin demonstrates similar potent inhibitory effects 1

Moderate CYP3A4 and/or P-glycoprotein Inhibitors

These cause less pronounced but still clinically relevant interactions:

• Erythromycin increases drug exposure by 1.3-fold 1
• Verapamil and diltiazem (calcium channel blockers) act as mechanism-based inhibitors 1, 2
• Cyclosporin is contraindicated with colchicine due to increased toxicity risk 1
• Quinidine modestly increases plasma concentrations of P-gp substrates 1
• Dronedarone is a strong P-gp inhibitor that can double dabigatran concentrations 1

Strong CYP3A4 Inducers

These agents significantly reduce drug exposure and efficacy:

Anticonvulsants

• Phenytoin, carbamazepine, and phenobarbital are potent inducers that should be avoided with most CYP3A4 substrates 1

Antimicrobials

• Rifampin causes a 50% decrease in rivaroxaban exposure and is the most potent inducer 1
• Rifabutin and rifapentin share similar inducing properties 1

Other Inducers

• Dexamethasone (at high doses) acts as a CYP3A4 inducer 1
• St. John's wort is a potent herbal inducer that must be avoided 1

Clinical Management Principles

With Apixaban

• Reduce dose from 5 mg twice daily to 2.5 mg twice daily when combined with strong dual CYP3A4/P-gp inhibitors 1, 3
• If already receiving 2.5 mg twice daily, avoid apixaban use entirely with strong inhibitors 1
• Avoid concomitant use with strong inducers 1

With Rivaroxaban

• Avoid use with combined strong CYP3A4 and P-gp inhibitors (ketoconazole, ritonavir, cobicistat) 1
• In patients with CrCl 15-80 mL/min receiving moderate inhibitors like erythromycin, avoid rivaroxaban due to significantly increased exposure 1
• Avoid use with strong inducers as they reduce efficacy 1

With Dabigatran

• Contraindicated with ciclosporin, itraconazole, ketoconazole, and tacrolimus 1
• Avoid use in patients with CrCl <30 mL/min if combined with strong P-gp inhibitors 1
• Stagger administration by 2 hours when using P-gp inhibitors to minimize peak concentration increases 1

With Edoxaban

• Consider switching to warfarin instead of dose reduction when strong P-gp inhibitors are needed, especially with CrCl <50 mL/min 1
• Avoid rifampin; effects of other inducers not well studied 1

With Colchicine

• Strong P-gp and/or CYP3A4 inhibitors (cyclosporin, clarithromycin, verapamil, ketoconazole, ritonavir) increase colchicine plasma concentrations and risk of serious toxicity 1
• Avoid colchicine entirely in patients with severe renal impairment (GFR <30 mL/min) receiving these inhibitors 1

Common Pitfalls to Avoid

• Do not overlook the dual inhibition requirement: Only drugs that inhibit both CYP3A4 AND P-gp cause the most significant interactions with factor Xa inhibitors 1
• Renal function amplifies interactions: Moderate inhibitors become clinically significant in patients with renal impairment due to reduced drug clearance 1
• Mechanism-based inhibition is irreversible: Drugs like clarithromycin, erythromycin, verapamil, and diltiazem cause prolonged enzyme inactivation requiring synthesis of new CYP3A4 2, 4, 5
• Grapefruit juice acts as a CYP3A4 inhibitor and should be avoided with susceptible drugs 1, 6
• Temporal relationships matter: Staggering administration by 2 hours can reduce P-gp-mediated interactions 1