Drug Interaction Risk: Metronidazole with Tacrolimus-Based Immunosuppression
Taking metronidazole 1 hour after tacrolimus carries significant risk of tacrolimus toxicity and requires close monitoring, but the timing separation of 1 hour does not mitigate this interaction—the concern is systemic drug metabolism, not absorption timing.
Critical Drug Interaction: Tacrolimus and Metronidazole
Metronidazole can substantially elevate tacrolimus blood levels, potentially causing nephrotoxicity and other serious adverse effects. 1
A documented case report showed tacrolimus trough concentrations increased from 7-10 ng/mL to 26.3 ng/mL within 4-14 days of starting metronidazole 500mg four times daily, with concurrent serum creatinine elevation from baseline 1.6-1.8 mg/dL to 3.3 mg/dL 1
The mechanism involves metronidazole's inhibition of CYP3A4 (the primary enzyme metabolizing tacrolimus) and possibly P-glycoprotein, both critical for tacrolimus clearance 1, 2
This interaction was classified as "probable" on the Naranjo probability scale 1
Why Timing Separation Doesn't Help
The 1-hour separation between doses is irrelevant for this interaction because the problem is metabolic, not absorptive:
- Tacrolimus is metabolized systemically by CYP3A4 in the liver and intestinal wall 2
- Metronidazole inhibits these enzymes throughout the body once absorbed, regardless of when tacrolimus was taken 1
- The interaction persists as long as both drugs are in the system simultaneously 1
No Significant Interactions with Other Medications
Mycophenolate mofetil and esomeprazole do not significantly interact with metronidazole:
- Mycophenolate mofetil does not significantly alter tacrolimus pharmacokinetics when coadministered 3
- Esomeprazole (a proton pump inhibitor) has no documented clinically significant interaction with metronidazole 4
Essential Monitoring Requirements
If metronidazole must be used with tacrolimus, implement intensive monitoring:
- Check tacrolimus trough concentrations every 2-3 days during metronidazole therapy 1
- Monitor serum creatinine closely for nephrotoxicity 1
- Anticipate need for tacrolimus dose reduction of 50-75% based on the case report (from 4mg twice daily to 1mg twice daily) 1
- After metronidazole discontinuation, tacrolimus levels may drop rapidly, requiring dose increases 1
Clinical Decision Algorithm
Consider these alternatives in order of preference:
First choice: Use an alternative antibiotic without CYP3A4 inhibition if clinically appropriate for the infection being treated 1
If metronidazole is essential: Proceed with metronidazole but implement the intensive monitoring protocol above, with preemptive tacrolimus dose reduction by approximately 50% 1
Never: Simply separate the doses by 1 hour and assume safety—this provides no protection 1, 2
Common Pitfall to Avoid
The most dangerous error is assuming that spacing medications by 1 hour prevents drug interactions. This only applies to absorption-based interactions (like certain antacids with antibiotics), not metabolic interactions involving CYP enzymes 2. With tacrolimus and metronidazole, the drugs interact systemically after both are absorbed, making timing of administration irrelevant 1.