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C A S E R E P O R T
Hellenic Journal of Atherosclerosis 1(1):65–67
Case report
of rhabdomyolysis possibly associated
to the interaction of ciprofloxacin with simvastatin
N. Fountoulakis, L. Khafizova, M. Logothetis,
G. Fanti, J.A. Papadakis
Department of Internal Medicine, University Hospital of Heraklion, Heraklion Crete, Greece, ΑΒSTRACT: This is a case report of rhabdomyolysis possibly associated to the administration of ciprofloxacin to a
patient on chronic lipid-lowering therapy with simvastatin. It is the second case report in the literature. We suggest a mechanism of interaction between the two agents which involves the adenosine-5'-triphosphate (ATP)-binding cassette drug efflux transporter family.
Key words: Ciprofloxacin, simvastatin, rhabdomyolysis, MRPs.
On physical examination he was feverless, pulse 77 Case report
beats per minute and blood pressure 144/95 mm Hg, A 55-year old man presented to the emergency proximal and distal muscle weakness with tenderness department (ER) with a 3-day history of muscle pain, to touch and no skin rash. fatigue and weakness. He had been on a 5-day course Haemochemistry analysis: creatine kinase (CK) with ciprofloxacin due to a urinary tract infection. He had not any vigorous physical activity the previous level (25,320 U/L), aspartate aminotransferase (AST) days. His past medical history included hypertension 846 U/L, alanine aminotransferase (ALT) 588 U/L, and percutaneous transluminal coronary angioplasty lactate dehydrogenase (LDH) 1,627 U/L, potassium (PTCA) 3 years ago. Since then he had been taking (K) 4.6 mEq/L, sodium (Na) 142 mEq/L, calcium (Ca) 9.5 carvedilol (3.125 mg b.i.d.), ramipril (5 mg o.d.) and mEq/l, phosphorous (P) 3.7 mEq/L. Haematocrit (Hct) simvastatin (40 mg o.d.). He was a smoker and worked 51.5%, haemoglobin (Hgb) 17.3 g/dL, white blood as a driver.
cell (WBC) 7.2 K/μL, platelets 225 K/μL, erythrocyte sedimentation rate (ESR) 6 mm/1st hour, C-reactive protein (CRP) 0.32 mg/dl, thyroid-stimulating hormone (TSH) 0.73 μUI/ml. Urine dipstick showed John A. Papadakis MD
1+protein and positive for myoglobin. Department of Internal Medicine, University Hospital of Heraklion, The working diagnosis was rhabdomyolysis. He P.O. Box 1352, Heraklion Gr-711 10, Greece received enough intravenous fluids (normal saline 3- Tel: 2810-39 26 88, Fax: 2810-39 23 59 e-mail: [email protected] 4 L/d), to have increased diuresis, along with NαHCO3 2013 HellenicJournal of Atherosclerosis 2013 HellenicJournal of Atherosclerosis N. Fountoulakis et al to alkalinize his urine. His CK level dropped to 1500 of myotoxicity when co-administered with statins. U/L on the fourth day of his admission. His symptoms Inhibitors of OATP1B1 may decrease the benefit/risk improved rapidly after the beginning of treatment.
ratio of statins by interfering with their entry into hepatocytes.4 Pravastatin's biliary excretion is mainly mediated by multidrug resistance-associated protein We assumed that the cause of rhabdomyolysis was the administration of ciprofloxacin to a patient who Ciprofloxacin is a weak inhibitor of CYP3A4 and a was on lipid lowering therapy with simvastatin. In the strong inhibitor of CYP1A2. Clearance of ciprofloxacin literature there is one case report of rhabdomyolysis from the body can be accelerated by MRP1 and due to the combination of these two agents.1 MRP2 transporters in the intestine, kidney, liver or The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG- central nervous system (CNS). MRP4 is the most likely CoA) reductase inhibitors (statins) are effective in both transporter of ciprofloxacin in murine macrophages the primary and secondary prevention of ischaemic but there is a possible common up-regulation heart disease. As a group these drugs are well tolerated, mechanism for both MRP4 and MRP2 upon chronic except for two uncommon adverse effects: elevation exposure of eukaryotic cells to this widely used of liver enzymes and skeletal muscle abnormalities which range from benign myalgias to life-threatening MRPs are anion efflux transporters, members of rhabdomyolysis. Adverse effects with statins are the ABC transporters superfamily. They are anergized frequently associated with drug interactions because by adenosine-5'-triphosphate (ATP) hydrolysis and of their long term use in older patients who are likely require glutathione as a cofactor. They have a wide to be exposed to polypharmacy.2 distribution within the human body and show Physical exercise appears to increase the likelihood broad specificity recognizing a large number of for the development of myopathy in patients taking statins. It has been shown that statins can induce A recent research has demonstrated that the MRP1, apoptosis in a variety of cell types including myocytes. Statin-induced apoptosis of healthy skeletal myocytes MRP4, MRP5 are expressed on the sarcolemmal may be a contributing factor causing myopathy. The membrane of human skeletal muscle fibers and that data support that statin-induced apoptosis is likely atorvastatin and rosuvastatin are substrates for these stimulated by isoprenoid depletion, resulting in transporters. The activity of MRP1 contributes to the a decrease of protein geranylgeranylation and/or reduction of intracellular statin accumulation within farnesylation, which in turn, may lead to elevated human skeletal myoblast cells in vitro.7 levels of cytosolie calcium and activation of We could hypothesize that there is an interaction mitochondrial-mediated apoptotic signalling.3 between simvastatin and ciprofloxacin at the level of Simvastatin, lovastatin, and atorvastatin are their transport through the MRP efflux transporters. me tabolized by cytochrome P450 (CYP 3A4) (sim- The competition of these two substances for the vastatin acid is also metabolized by CYP2C8); their same transporters could increase the concentration plasma concentrations and risk of myotoxicity are of statin in the plasma or within the muscle skeletal greatly increased by strong inhibitors of CYP3A4 cell resulting in myopathy (rhabdomyolysis in our (eg, itraconazole and ritonavir). Cyclosporine (INN, ciclosporin) inhibits CYP3A4, P-glycoprotein (multidrug resistance protein 1), organic anion In conclusion, this is the second published report transporting polypeptide 1B1 (OATP1B1), and some of this uncommon interaction between statins and other hepatic uptake transporters. Gemfibrozil and a quinolone. Since rhabdomyolysis is a potentially its glucuronide inhibit CYP2C8 and OATP1B1. These life threatening condition, medical professionals effects of cyclosporine and gemfibrozil explain the should be aware of the risk of this combination. This increased plasma statin concentrations and, together interaction has been reported to the Greek National with pharmacodynamic factors, the increased risk Organization for Medicines.
2013 HellenicJournal of Atherosclerosis CIPROFLOXACIN PLUS SIMVASTATIN ASSOCIATED RHABDOMYOLYSIS fluoroquinolone antibiotic ciprofloxacin in murine macrophages: studies with ciprofloxacin-resistant cells. Antimicrob Agents 1. Sawant RD. Rhabdomyolysis due to an uncommon interaction of Chemother 2009, 53:2410–2416 ciprofloxacin with simvastatin. Can J Clin Pharmacol 2009, 16:78– 6. Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y. Physiologically based pharmacokinetic modeling to predict Williams D, Feely J. Pharmacokinetic-pharmacodynamic transporter-mediated clearance and distribution of pravastatin in drug interactions with HMG-CoA reductase inhibitors. Clin humans. J Pharmacol Exp Ther 2009, 328: 652–662 Pharmacokinet 2002, 41:343–370 7. Knauer MJ, Urquhart BL, Meyer zu Schwabedissen HE et al. Human 3. Dirks AJ, Jones KM. Statin-induced apoptosis and skeletal myopathy. skeletal muscle drug transporters determine local exposure and Am J Physiol Cell Physiol 2006, 291:1208–1212 toxicity of statins. Circ Res 2010, 106:297–306 4. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid- lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006, 80:565–581 5. Marquez B, Caceres NE, Mingeot-Leclercq MP, Tulkens PM, Submitted 27/06/2013 Van Bambeke F. Identification of the efflux transporter of the Accepted 04/09/2013 2013 HellenicJournal of Atherosclerosis

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