Ketoconazole is the Strong CYP3A4 Inhibitor

Among the drugs listed (rifampin, azithromycin, ketoconazole, amoxicillin, metformin), ketoconazole is the only strong CYP3A4 inhibitor. 1

Classification of Each Drug

Ketoconazole is classified as a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2C19. 1
It can cause clinically significant increases in plasma concentrations of CYP3A4 substrate drugs, potentially leading to serious adverse effects including cardiac arrhythmias, rhabdomyolysis, and organ toxicity. 1, 2
Ketoconazole is frequently used as the reference standard drug in pharmacokinetic studies to evaluate CYP3A4 inhibition. 3
Concomitant use with many CYP3A4 substrates is contraindicated, including certain anticoagulants (rivaroxaban, apixaban), immunosuppressants (cyclosporine, tacrolimus), and chemotherapeutic agents. 1

Rifampin is a strong CYP3A4 inducer, not an inhibitor—it has the opposite effect of ketoconazole. 1
It significantly decreases plasma concentrations of CYP3A4 substrates by increasing their metabolism, leading to reduced drug efficacy. 1, 4
Rifampin also induces CYP2C9, further broadening its drug interaction profile. 1
Must be avoided with drugs requiring consistent CYP3A4-mediated metabolism such as direct oral anticoagulants, protease inhibitors, and many chemotherapeutic agents. 1, 4

Azithromycin has minimal to no clinically significant effect on CYP3A4. 4, 3
Unlike other macrolides (clarithromycin, erythromycin), azithromycin does not cause meaningful CYP3A4 inhibition. 3
It is considered a safe alternative when macrolide therapy is needed in patients taking CYP3A4 substrates. 3

Amoxicillin does not interact with CYP3A4 as it is not metabolized by this enzyme system. 4
It is primarily eliminated renally and does not affect P-glycoprotein transport. 4
Amoxicillin can be safely used with CYP3A4 substrates without dose adjustment concerns. 1

Metformin is not metabolized by CYP3A4 and does not inhibit or induce this enzyme. [@general medical knowledge@]
It is eliminated unchanged in the urine and does not participate in cytochrome P450-mediated drug interactions. [@general medical knowledge@]

Hypoalbuminemia increases the free (unbound) fraction of highly protein-bound drugs, leading to increased volume of distribution and clearance. 5, 6
When a strong CYP3A4 inhibitor like ketoconazole is added, it blocks the metabolism of CYP3A4 substrates, causing drug accumulation despite altered protein binding. 5
This creates a "double hit" scenario: increased free drug from hypoalbuminemia plus decreased clearance from CYP3A4 inhibition, substantially raising toxicity risk. 5, 6

Highly protein-bound antibiotics (ceftriaxone, ertapenem, teicoplanin) already have 2-fold increases in volume of distribution and clearance with hypoalbuminemia alone. 5
Direct oral anticoagulants (rivaroxaban, apixaban) require dose reduction or avoidance when combined with ketoconazole due to 2.3-fold increases in drug exposure. 1
Immunosuppressants (cyclosporine, tacrolimus) are contraindicated with ketoconazole due to severe toxicity risk. 1

Do not confuse rifampin as an inhibitor—it is a potent inducer that decreases drug levels, requiring the opposite management approach. 1, 4
Do not assume all macrolides inhibit CYP3A4—azithromycin is the exception and does not cause clinically significant inhibition. 3
Do not overlook the time course of CYP3A4 induction with rifampin—full enzyme induction takes 2-4 weeks to develop and persists 2-4 weeks after discontinuation. 1
Remember that ketoconazole inhibition is immediate and profound, unlike the gradual effect of inducers. 2, 7