Interactions between Tacrolimus and Metronidazole in a renal transplant patient

• Authors: Aleksandra Catic-Djordjevic , Radmila Velickovic-Radovanovic , Nikola Stefanovic , Tatjana Cvetkovic
• Languages of publication: EN

Abstracts

EN

We present a case which reports the occurrence of a potential elevation of Tacrolimus (Tac) plasma levels to toxic values in a renal transplant recipient after adding Metronidazole (Met) to the medication regimen. A 30-year old female, status post living-related renal transplant, who was stabilized on Tac 4.5 mg, twice daily, for 4 months, presented to the clinic with diarrhea. We used Microparticle Enzyme Immunoassay (MEIA) to determine Tac trough concentration (trough concentrations 5–10 ng/ml). After 6 days of Met therapy on 1.5 g/d, Tac trough concentration and serum creatinine (sCr) increased to 20.2 ng/ml and 7.8 mg/dl respectively. Met therapy was discontinued, also one dose of Tac was withheld, while daily dose was decreased to 2 mg/d. Four days after Met discontinuation, Tac concentration dropped to 8.7 ng/ml, sCr to 2.1 mg/dl, warranting Tac dose increase to 3 mg/d. Co-administration of Tac with Met may result in elevated Tac concentrations, possibly leading to tacrolimus nephrotoxicity. Clinicians should be aware of this potential interaction and closely monitor Tac concentration and renal function.

Keywords

EN

Interactions; Metronidazole; Tacrolimus; Renal transplantation

• Publisher: De Gruyter Open
• Journal: Open Medicine
• Year: 2012
• Volume: 7
• Issue: 5
• Pages: 587-590

Dates

published

1 - 10 - 2012

online

28 - 7 - 2012

Contributors

author

Aleksandra Catic-Djordjevic

• Medical Faculty, University of Nis, 18000, Nis, Serbia

author

Radmila Velickovic-Radovanovic

author

Nikola Stefanovic

• Medical Faculty, University of Nis, 18000, Nis, Serbia

author

Tatjana Cvetkovic

References

• [1] Chen Y, Yheng K, Chen L, et al. Clinical pharmacokinetics of tacrolimus after the first oral administration in combination with mycophenolate mofetil and prednisone in Chinese kidney transplantation recipients. Transplant Proc 2005; 37:4246–4250 http://dx.doi.org/10.1016/j.transproceed.2005.11.055[Crossref]
• [2] Dai Y, Hebert MF, Isoherranen N, et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos 2006; 34:836–847 http://dx.doi.org/10.1124/dmd.105.008680[Crossref]
• [3] Masuda S, Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Therapeut 2006; 112:84–98 http://dx.doi.org/10.1016/j.pharmthera.2006.04.006[Crossref]
• [4] Filler G, Grygas R, Mai I, et al. Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants. Nephrol Dial Transp 1997; 12:1668–1671 http://dx.doi.org/10.1093/ndt/12.8.1668[Crossref]
• [5] Keven K, Basu A, Re L, et al. Clostridium difficile colitis in patients after kidney and pancreas-kidney transplantation. Transpl Infect Dis 2004; 6:10–14. http://dx.doi.org/10.1111/j.1399-3062.2004.00040.x[Crossref]
• [6] Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect 2009; 58:403–410 http://dx.doi.org/10.1016/j.jinf.2009.03.010[Crossref][WoS]
• [7] Löfmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis 2010; 50:16–23 http://dx.doi.org/10.1086/647939[Crossref]
• [8] Cooke CE, Sklar GE, Nappi JM. Possible pharmacokinetic interaction with quinidine: ciprofloxacin or metronidazole? Ann Pharmacother 1996; 30:364–366 [PubMed]
• [9] Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet 1996; 31:198–214 http://dx.doi.org/10.2165/00003088-199631030-00004[Crossref]
• [10] Dilger K, Fux R, Röck D, et al. Effect of High-Dose Metronidazole on Pharmacokinetics of Oral Budesonide and Vice Versa: A Double Drug Interaction Study. J Clin Pharmacol 2007; 47:1532 http://dx.doi.org/10.1177/0091270007308617[WoS][Crossref]
• [11] Page RL 2nd, Klem PM, Rogers C. Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother 2005; 39: 1109–1113 http://dx.doi.org/10.1345/aph.1E399[Crossref]
• [12] Herzig K, Johnson DW. Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy. Nephrol Dial Transplant 1999; 14:521–523 http://dx.doi.org/10.1093/ndt/14.2.521b[Crossref]
• [13] Drug interactions between tacrolimus and metronidazole. Drugs.com. [accesed, 26 december 2011]. Available from: http://www.drugs.com/drug-interactions/metronidazole-with-tacrolimus-2142-0-1617-0.html
• [14] Vincent F, Glotz D, Kreft-Jais C, et al. Acute kidney failure in a patient treated with cyclosporine A and metronidazole following kidney transplantation. Therapie 1994; 49:155
• [15] Zylber-Katz E, Rubinger D, Berlatzky Y. Cyclosporine interactions with metronidazole and cimetidine. Drug Intell Clin Pharm 1988; 22:504–505.
• [16] Mendes J, Martinho A, Simoes O, et al. Genetic polymorphisms in CYP3A5 and MDR1 genes and their correlations with plasma levels of tacrolimus and cyclosporine in renal transplant recipients. Transplant Proc 2009; 41: 840–842 http://dx.doi.org/10.1016/j.transproceed.2009.01.050[Crossref]
• [17] Loh PT, Lou HX, Zhao Y, et al. Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. Transplant Proc 2008; 40(5):1690–1695 http://dx.doi.org/10.1016/j.transproceed.2008.04.010[WoS][Crossref]
• [18] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2): 239–245 http://dx.doi.org/10.1038/clpt.1981.154[Crossref]
• [19] Roedler R, Neuhauser MM, Penzak SR. Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? Ann Pharmacother 2007;41(4):653–658 http://dx.doi.org/10.1345/aph.1H401[WoS][Crossref]
• [20] Wang JS, Backman JT, Kivistö KT, et al. Effects of metronidazole on midazolam metabolism in vitro and in vivo. Eur J Clin Pharmacol 2000; 56(8):555–559 http://dx.doi.org/10.1007/s002280000201[Crossref]
• [21] Michalets EL, Williams CR. Drug interactions with cisapride: clinical implications. Clin Pharmacokinet 2000; 39(1): 49–75 http://dx.doi.org/10.2165/00003088-200039010-00004[Crossref]
• [22] Drug Development and Drug Interactions.U.S. Food and Drug Administration [accesed, 26 december 2011]. Available from: http://www. fda.gov/Drugs/DevelopmentApprovalProcess/ D e v e l o p m e n t R e s o u r c e s / DrugInteractionsLabeling/ucm091806.htm
• [23] Guideline on the Investigation of Drug Interactions. European Medicines Agency. [accesed, 26 december 2011]. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf

Identifiers

DOI

10.2478/s11536-012-0035-7