Abstract
Concomitant administration of atorvastatin, omeprazole, and dexamethasone has been shown to increase the serum concentration of serum hydroxymethylglutaryl coenzyme A which can be associated with elevation of creatine kinase and an increased risk of severe myopathy and rhabdomyolysis. In this paper, we report a case of a 60-year-old female patient with stage IV colon cancer and compromised hepatic function receiving palliative care who developed rhabdomyolysis while taking atorvastatin, omeprazole, and dexamethasone. Atorvastatin was stopped, and the dexamethasone dose was decreased. Her case was complicated by urosepsis cultures revealing an extended spectrum β-lactamase-producing strain of Escherichia coli, and she died on the second day after admission. Physicians should evaluate the risk/benefit ratio of continuing statins in palliative care patients, and pay special attention to the monitoring of patients on statins and P-glycoprotein inhibitors regardless of hepatic function.
Introduction
Rhabdomyolysis is a clinical syndrome in which skeletal muscle damage and necrosis leads to the release of intracellular contents of muscle. In severe cases, this can lead to extreme serum muscle enzyme elevations, electrolyte imbalances, renal failure, and death.Citation1 The most common side effects of statins are skeletal muscle complaints, including clinically important myositis and rhabdomyolysis, mild serum creatine kinase elevations, myalgia with or without elevated creatine kinase, muscle weakness, muscle cramps, and persistent myalgia.Citation2 The risk of rhabdomyolysis and other adverse effects of statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications.Citation2 Herein, we report a case of rhabdomyolysis due to concomitant administration of dexamethasone and omeprazole with atorvastatin in a patient without any precipitating factors.
Case report
A 60-year-old female patient on palliative care and known to have stage IV colon cancer with metastasis to the omentum, mesentery, bone and lung, as well as a focal hepatic lesion in segment VIII, was admitted to hospital with complaints of shortness of breath, lethargy, severe myalgia, and proximal muscle weakness of the extremities. A computed tomographic angiogram was done, which ruled out pulmonary embolism. She denied alcohol use, and vigorous physical exercise was very unlikely given her palliative care status. Her medications consisted of atorvastatin 20 mg daily for hyperlipidemia which she had been taking for the previous 6 months, omeprazole 20 mg daily for peptic ulcer prophylaxis, dexamethasone 8 mg twice daily for spinal cord compression, calcium carbonate supplementation, tramadol for chronic cancer pain, celecoxib for bone pain, gabapentin for neuropathic pain, and bisacodyl for constipation. She had no prior personal history of thyroid disease or muscle disorders. She had no previous history of muscular toxicity with statin or fibrate use. shows the patient’s laboratory values on admission and 1 day after admission.
The diagnosis was rhabdomyolysis secondary to a drug interaction between omeprazole, dexamethasone, and atorvastatin. Atorvastatin was stopped, the dexamethasone dose was decreased to 6 mg twice daily, and intravenous fluids were started immediately. Her case was complicated by urosepsis cultures revealing an extended spectrum β-lactamase-producing strain of Escherichia coli, and she died on the second day after admission.
Discussion
This report describes a patient with rhabdomyolysis secondary to a drug interaction between atorvastatin, omeprazole, and dexamethasone. Statins have been found to be effective in both primary and secondary prevention of coronary disease.Citation3 Although statins are well tolerated by most patients, they may cause myopathy, rhabdomyolysis, and elevated liver enzymes.Citation4 Proton pump (P-glycoprotein) inhibitors may increase serum hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor concentrations.Citation5 At the same time, dexamethasone (a P-glycoprotein PGP/ABCB1 inhibitor) may increase serum concentrations of P-glycoprotein PGP/ABCB1 substrates like atorvastatin. P-glycoprotein inhibitors may also enhance the distribution of P-glycoprotein substrates to specific cells, tissues, and organs where P-glycoprotein is present in large amounts, eg, the brain, T lymphocytes, and the testes.Citation6,Citation7 However, data are conflicting regarding the role of P-glycoprotein in the disposition of atorvastatin,Citation8–Citation11 and the ability of proton pump inhibitors such as omeprazole to inhibit P-glycoprotein at therapeutic concentrations.Citation12,Citation13 There have been several case reports of rhabdomyolysis induced by medications which increase the serum concentration of HMG-CoA reductase inhibitors,Citation4–Citation7 but most of the reported cases were precipitated by exercise.Citation14,Citation15 Increased serum HMG-CoA concentrations can be associated with elevation of creatine kinase and an increased risk of severe myopathy and rhabdomyolysis. Due to the severe morbidity seen in this report, close monitoring is warranted when such agents are used in combination. In addition, given that many statins are substrates of P-glycoprotein, this mechanism needs further elaboration to prevent similar complications with use of this important class of drugs.
Conclusion
P-glycoprotein drug interactions with atorvastatin and other HMG-CoA reductase inhibitors, ie, statins, may be associated with unreported risks for rhabdomyolysis. Critical monitoring is warranted when such agents are used in combination. In addition, since many statins are substrates of P-glycoprotein, this mechanism needs further elaboration to prevent similar complications with use of this important class of drugs.
Disclosure
The authors declare no conflicts of interests in this work.
References
- TokinagaKOedaTSuzikiYMatsushimaYHMG CoA reductase inhibitors might cause high elevations of creatine phosphokinase in patients with unnoticed hypothyroidismEndocr J20065340140516723812
- ThompsonPDClarksonPKarasRHStatin-associated myopathyJAMA20032891681169012672737
- LarosaJCHeJVupputuriSEffect of statins on risk coronary diseaseJAMA19992822340234610612322
- OmarMAWillsonJPCoxTSRhabdomyolysis and HMG-COA reductase inhibitorsAnn Pharmacother2001351096110711573861
- SipeBEJonesRJBokhartGHRhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interactionAnn Pharmacother20033780881112773066
- KivistoKTNiemiMFrommMFFunctional interaction of intestinal CYP3A4 and P-glycoproteinFundam Clin Pharmacol20041862162615548232
- KimRBDrugs as P-glycoprotein substrates, inhibitors, and inducersDrug Metab Rev200234475411996011
- ChenCLinJSmolarekTP-glycoprotein has differential effects on the disposition of statin acid and lactone forms in Mdr1a/B knockout and wild-type miceDrug Metab Dispos2007351725172917640956
- ChenCMirelesRJCampbellSDDifferential interaction of 3-hydroxy-3-methylglutaryl-CoAreductase inhibitors with ABCB1, ABCC2, and OATP1b1Drug Metab Dispos20053353754615616150
- HochmanJHPudvahNQiuJInteractions of human P- glycoprotein with simvastatin, simvastatin acid, and atorvastatinPharm Res2004211686169115497697
- WuXWhitfieldLRStewartBHAtorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporterPharm Res20001720921510751037
- Pauli-MagnusCRekersbrinkSKlotzUInteraction of omeprazole, lansoprazole and pantoprazole with P-glycoproteinNaunyn Schmiedebergs Arch Pharmacol200136455155711770010
- CollettATanianis-HughesJCarlsonGLComparison of P-glycoprotein-mediated drug-digoxin interactions in Caco-2 with human and rodent intestine: relevance to in vivo predictionEur J Pharm Sci20052638639316153812
- BarahonaMJMauriASucuzzaNParedesRWangerAMHypothroidism as a cause of rhabdomyolysisEndocr J20024962162312625411
- RiggsJEAcute exertional rhabdomyolysis in hypothyroidism: the result of reversible defect in glycogenolysisMil Med19901551711722110339