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Resident, Faculty of Medicine, Department of Internal Medicine, Hacettepe University, Ankara, Turkey
Resident, Faculty of Medicine, Department of Internal Medicine, Hacettepe University
Resident, Faculty of Medicine, Department of Internal Medicine, Hacettepe University
Fellow, Faculty of Medicine, Medical Intensive Care Unit, Hacettepe University
Associate Professor, Faculty of Medicine, Department of Pharmacology, Hacettepe University
Associate Professor, Faculty of Medicine, Medical Intensive Care Unit, Hacettepe University
Reprints: Dr. Topeli, Department of Internal Medicine, Medical Intensive Care Unit, Hacettepe University, 06100, Ankara, Turkey, fax 90 312 305 2711, atopeli{at}hacettepe.edu.tr
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CASE SUMMARY: A 45-year-old man with nephrotic syndrome and amyloidosis presented with dyspnea, altered mentation, and severe fatigue. He had been taking colchicine 1.5 mg/day for amyloidosis for 3 years without adverse effects. Atorvastatin 10 mg/day was prescribed for hypercholesterolemia one month prior to admission. After 2 weeks of atorvastatin treatment, he began to experience myalgia and reduced muscle strength. The creatinine and creatine kinase concentrations on admission were 8.1 mg/dL and 9035 U/L, respectively. The patient was diagnosed with rhabdomyolysis with the findings of myoglobinuric, oliguric acute renal failure, and more than 50-fold elevated creatine kinase concentration. His muscle strength improved after withdrawal of atorvastatin and colchicine. However, he died because of nosocomial pneumonia that developed during his hospital stay. The Naranjo probability scale indicated that atorvastatin and colchicine were probable causes of rhabdomyolysis.
DISCUSSION: Atorvastatin and colchicine have well-known myotoxic adverse effects. Despite atorvastatin's proven safety, its use with certain drugs, such as colchicine, makes it a potential myotoxic drug. This might be because concomitant administration of P-glycoprotein substrates, such as statins, and colchicine, which is a P-glycoprotein inhibitor, modifies pharmacokinetics by increasing bioavailability and organ uptake of the substrates, leading to more adverse reactions and toxicities.
CONCLUSIONS: We recommend checking the creatine kinase level one week after prescribing 2 or more potentially myotoxic drugs concomitantly, after dose increase of a myotoxic drug, or after prescribing a new drug to a patient already using other myotoxic agents.
Key Words: atorvastatin, colchicine, P-glycoprotein, rhabdomyolysis
Published Online, June 13, 2006. www.theannals.com, DOI 10.1345/aph.1H064
Although acute myopathy or rhabdomyolysis due to concomitant use of colchicine and simvastatin, pravastatin, or fluvastatin has been reported,9-12 rhabdomyolysis due to concomitant use of colchicine and atorvastatin, as of June 6, 2006, has not yet been reported. We present a case of rhabdomyolysis due to concurrent use of colchicine and atorvastatin in a patient with amyloidosis and nephrotic syndrome.
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On admission, physical examination revealed blood pressure 120/85 mm Hg, heart rate 110 beats/min, respiratory rate 30 breaths/min, and temperature 36 °C, as well as mental confusion, bilateral fine crackles in the lungs, barrel-shaped chest, moderate peripheral edema, and dark urine. Complete blood cell count indicated leukocytosis (Table 1). Urinalysis was consistent with myoglobinuria. Thyroid hormone levels were normal (thyroid-stimulating hormone, 1.7 µU/mL [reference range 0.27-4.2]; parathyroid hormone, 69 pg/mL [9.5-75]), and autoimmune markers and viral screening did not reveal any pathology. The patient's serum theophylline concentration was 3.95 µg/mL (10-20).
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After admission, emergent hemodialysis was started due to oliguric acute renal failure, serious electrolyte disturbances, and hypervolemia. His mental status improved with hemodialysis and ventilatory support. Neurologic examination performed after mental recovery revealed marked symmetrical proximal muscle weakness that was worse in the lower extremities (grade 3/5 for upper limbs, 2/5 for lower limbs; Medical Research Council Scale: 5 = full muscle strength, 3 = able to move the extremity against gravity, 2 = unable to move the extremity against gravity). Motor and sensory findings of the distal limbs were normal, and a slightly delayed relaxation in the deep-tendon reflexes was observed.
Rhabdomyolysis was diagnosed on clinical and biochemical grounds, including a more than 50-fold increase in creatine kinase concentration and accompanying myoglobinuric acute oliguric renal failure. Concomitant use of colchicine and atorvastatin was thought to be the cause. After withdrawal of colchicine and atorvastatin, creatine kinase and myoglobin levels gradually decreased, and the patient's muscle strength improved. However, he became dependent on hemodialysis, developed septic shock due to nosocomial pneumonia, and died on hospital day 18 due to refractory septic shock and respiratory failure.
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Atorvastatin exhibits unique pharmacokinetic properties among the statins. It is subject to extensive first-pass metabolism and has a mean elimination half-life of 14 hours, which is the longest among the statins.2-4 Unlike pravastatin and fluvastatin, but similar to simvastatin, atorvastatin is metabolized by CYP3A4 to 2 relatively longer acting metabolites.3,4 CYP3A4, the major isoform of the CYP3A subfamily, is one of the most important drug metabolizing enzymes due to its extremely broad substrate specificity and involvement in the metabolism of about 50% of drugs currently used in humans.4 Biliary excretion is the major route of elimination, whereas its renal excretion is negligible.3,4 In vitro, atorvastatin and its metabolites interact as a substrate as well as an inhibitor with P-gp and other transporters such as organic anion-transporting polypeptide C.2-4,7,8
Colchicine, which has a narrow therapeutic index, shares many pharmacologic features with atorvastatin. Similar to atorvastatin, colchicine is subject to extensive metabolism in the liver, mediated mainly by CYP3A4, and it interacts with P-gp.5 Unlike atorvastatin, excretion of colchicine occurs from both the liver and the kidney. Because both drugs are metabolized via CYP3A4, increased accumulation of the metabolites leads to increased potential for adverse reactions when the drugs are used together. Given that colchicine and atorvastatin are metabolized through the same pathway, one might speculate that other statins (ie, fluvastatin or pravastatin), which are metabolized differently, would have been preferred.9 However, reports of interactions of colchicine with pravastatin11 and fluvastatin12 indicate the contribution of a mechanism different from the CYP3A4 pathway for the occurrence of these interactions.
Although we cannot definitively rule out the possibility that rhabdomyolysis developed solely due to atorvastatin or colchicine, several factors lead us to hypothesize that it occurred due to the concomitant use of colchicine and atorvastatin. First, given that our patient had been using colchicine for about 3 years with no adverse effects, it is unlikely to have been the only cause of rhabdomyolysis.13 As has been reported,13 although myopathy is a well known complication of colchicine therapy, there are few reported cases of rhabdomyolysis attributed to colchicine alone, and prolonged duration of colchicine therapy is not as important in the development of rhabdomyolysis as the doses administered and the underlying diseases. In that report, all colchicine-associated rhabdomyolysis (not myopathy) cases involved patients who had been taking colchicine for days or several weeks rather than years, with one exception, which involved a renal transplant recipient receiving cyclosporine therapy. Second, although myopathy is a major adverse effect associated with statin therapy in general, atorvastatin is considered safe even in very high doses (up to 80 mg/day). Myopathy has been reported in only 0.04 cases per million prescriptions and is considered to be dose-dependent.1 Rhabdomyolysis was observed in our patient only after low-dose atorvastatin (10 mg/day) was added to his drug therapy. Therefore, it is likely that rhabdomyolysis was caused by the combined effect of the 2 drugs.
In our patient, renal dysfunction was not considered to be a risk factor for the development of rhabdomyolysis because, although he had nephrotic syndrome, his renal function test results were within normal limits before admission (Table 1). Another possible cause of rhabdomyolysis is theophylline therapy, which may also cause myopathy.14,15 However, all reported cases of myopathy associated with theophylline therapy have been either due to overdose/poisoning or related to an acute asthmatic condition. Regarding our patient, normal theophylline concentration excludes intoxication. Our patient had taken theophylline and colchicine for 3 years with no adverse effects. Moreover, no interaction of theophylline with either atorvastatin or colchicine has been reported as of June 6, 2006. Use of the Naranjo probability scale indicated a probable relationship between rhabdomyolysis and concomitant atorvastatin-colchicine therapy.16
P-gp encoded by the human MDR1 gene serves as a cellular efflux transporter by removing xenobiotics from cells.6 P-gp has broad substrate specificity and is able to extrude a wide variety of chemically different xenobiotics.8 It is seen in the liver, intestines, kidney, placenta, blood-brain barrier,6,8 and skeletal muscle.17 Due to its intracellular localization, P-gp has a greater impact on drug uptake than excretion and plays a major role in detoxification and uptake in certain tissues such as the blood-brain barrier, placenta, and gut.6 P-gp and the CYP3A4 isoenzyme have many common features. For example, most of the P-gp substrates are also substrates of CYP3A4.4,6,18 However, it should be noted that this relationship is not complete, because some drugs are transported by P-gp but are not metabolized by CYP3A4 (eg, digoxin), and some compounds are CYP3A4 substrates but are not P-gp substrates (eg, midazolam).6,8,18 P-gp inhibition by both colchicine and statins, possibly causing accumulation of the metabolites in myocytes, could be another cause of rhabdomyolysis in our patient. Indeed, colchicine inhibits P-gp,18 which could lead to accumulation of statin concentrations within myocytes and, consequently, to the development of myotoxicity in susceptible individuals. Further indirect evidence of this theory is the interaction of colchicine with pravastatin.11 It should be remembered that pravastatin is not a substrate for CYP3A4.4,8 Supporting our observations and opinions, Wilbur and Makowsky13 reported that colchicine use with certain drugs, such as lipid-lowering agents, cyclosporine, and erythromycin, which are substrates of CYP3A4 and/or P-gp, might lead to the development of rhabdomyolysis. Indeed, the role of this transporter in drug-drug interactions is still poorly studied, although many P-gp substrates and inhibitors are identified among commonly used drugs.18 More studies are required to show direct evidence regarding the role of P-gp and other transport proteins in interactions of statins with other drugs.
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