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Potential Elevation of Tacrolimus Trough Concentrations with Concomitant Metronidazole Therapy

added qualifications in cardiology, Assistant Professor, Department of Clinical Pharmacy, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO; Clinical Specialist, Division of Cardiology/Heart Transplant, University of Colorado Hospital, Denver

Patrick M Klem, PharmD BCPS

Clinical Pharmacy Specialist, Renal Transplantation, Department of Pharmacy, University of Colorado Hospital

Christin Rogers, PharmD

Clinical Pharmacy Coordinator, Department of Solid Organ Transplant, Beth Israel Deaconess Medical Center, Boston, MA

Reprints: Dr. Page, UCHSC, School of Pharmacy, Department of Clinical Pharmacy, 4200 E. Ninth Ave., Box C238, Denver, CO 80262-0001, fax 303/315-4630, robert.page{at}uchsc.edu

OBJECTIVE: To report the occurrence of a potential tacrolimus elevation in a renal transplant recipient after adding metronidazole to the medication regimen.

CASE SUMMARY: A 24-year-old white man status post living-related renal transplant who had been stabilized on tacrolimus 4 mg twice daily (trough concentrations 7-10 ng/mL) for 2 months and prednisone 20 mg daily presented to the clinic with severe diarrhea. Stool cultures were positive for Clostridium difficile, and therapy with metronidazole 500 mg 4 times daily was initiated. Between days 4 and 14 of metronidazole therapy, the patient's tacrolimus trough concentration and serum creatinine level increased to maximum levels of 26.3 ng/mL and 3.3 mg/dL (baseline 1.6-1.8 mg/dL), respectively. Tacrolimus was withheld for one dose and then decreased to 1 mg twice daily. Two days after metronidazole discontinuation, tacrolimus trough concentrations dropped to 9.4 ng/mL and serum creatinine to 2.3 mg/dL, warranting a tacrolimus dose increase to 3 mg daily.

DISCUSSION: As of April 15, 2005, one other case has been reported documenting an elevation in tacrolimus concentrations with the addition of metronidazole. The possible mechanism may be related to metronidazole's weak inhibition of CYP3A4 and, possibly, P-glycoprotein. According to the Naranjo probability scale, metronidazole was the probable cause of this adverse reaction.

CONCLUSIONS: Coadministration of tacrolimus with metronidazole may result in elevated tacrolimus concentrations, possibly leading to tacrolimus toxicity. Practitioners should be aware of this potential interaction and closely monitor tacrolimus concentrations and renal function.

Key Words: interactions, metronidazole, tacrolimus

Published Online, April 26, 2005. www.theannals.com, DOI 10.1345/aph.1E399

This article has been cited by other articles:

				K. Dilger, R. Fux, D. Rock, K. Morike, and C. H. Gleiter Effect of High-Dose Metronidazole on Pharmacokinetics of Oral Budesonide and Vice Versa: A Double Drug Interaction Study J. Clin. Pharmacol., December 1, 2007; 47(12): 1532 - 1539. [Abstract] [Full Text] [PDF]

				R. Roedler, M. M Neuhauser, and S. R Penzak Does Metronidazole Interact with CYP3A Substrates by Inhibiting Their Metabolism Through This Metabolic Pathway? Or Should Other Mechanisms Be Considered? Ann. Pharmacother., April 1, 2007; 41(4): 653 - 658. [Abstract] [Full Text] [PDF]