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Possible Differences Between Fibrates in Pharmacokinetic Interactions With Statins

Possible Differences Between Fibrates in Pharmacokinetic Interactions With Statins The combination of a fibric acid derivative (fibrate) and a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) may offer a therapeutic advantage to patients with combined hyperlipidemia who respond inadequately to either agent alone. However, physicians remain reluctant to prescribe statins and fibrates concomitantly because of their concern that drug-drug interactions will increase the probability of muscle damage. Fibrates have been shown to increase statin plasma concentrations and to be associated with an increased risk of severe myopathy and rhabdomyolysis when prescribed in combination with a statin.1,2 The question of whether the increase in risk is due to a class effect for all fibrate-statin combinations remains unanswered. In our review of the risk of myopathy with statin therapy, we presented information on fibrate-statin interactions.3 At the time of the writing of this article, several studies had shown that gemfibrozil use increases plasma concentration of statins.4 In contrast, use of fenofibrate—another commonly prescribed fibric acid derivative—did not appear to affect the plasma concentration of pravastatin.5 The mechanism of this differential interaction of fibrates on statin metabolism was not well understood. The recent identification of a major metabolic pathway for statins and findings from a new pharmacokinetic study provide important insight into the mechanism of the observed interaction between gemfibrozil and statins. Glucuronidation has recently been identified as a major pathway for statin clearance. It has been demonstrated that gemfibrozil inhibits glucuronidation, thereby increasing the concentration of the active statin acid.6 This inhibition is most marked with cerivastatin sodium, the statin associated with most reports of myopathy and rhabdomyolysis, which was withdrawn from the market in August 2001 because of concerns about adverse events. A new report by Prueksaritanont et al7 indicated that there might be potential differences between fibrates in their ability to affect the glucuronidation pathway. In this study, Prueksaritanont and colleagues assessed the effects of gemfibrozil and fenofibrate on statin metabolism in human hepatocytes. Gemfibrozil was not only found to moderately interact with the CYP3A4 pathway but was also found to be a strong inhibitor of the glucuronidation-mediated lactonization of several statins. In contrast, fenofibrate showed a minimal effect on all metabolic pathways, including the statin glucuronidation. These findings were confirmed in another study that examined the effect of the coadministration of fenofibrate with rosuvastatin calcium on pharmacokinetic properties of rosuvastatin, a new statin recently approved in the United States.8 No changes were observed in the pharmacokinetic properties of either agent when concomitantly administered. We believe that these data are important for understanding the drug interactions observed between statins and gemfibrozil and highlight the differences between the fibrates in their interaction with statin metabolism. The lack of observed metabolic interaction between fenofibrate and statins suggests that the fenofibrate-statin combination may be a safer treatment approach than the gemfibrozil-statin combination for cardiovascular risk reduction in patients with combined hyperlipidemia. Dr Ballantyne has received grant/research support from AstraZeneca, Merck & Co Inc, Pfizer Inc, Novartis, Reliant, Schering-Plough, GlaxoSmithKline, and diaDexus Inc; served as a consultant for AstraZeneca, Merck & Co Inc, Pfizer Inc, Novartis, Reliant, and Schering-Plough; and participated on the speaker's bureau for AstraZeneca, Merck & Co Inc, Pfizer Inc, Novartis, Reliant, Schering-Plough, KOS Pharmaceuticals Inc, Bristol-Myers Squibb and Sanofi-Synthelabo. Dr Davidson has received grant/research support from Merck & Co Inc, Pfizer Inc, AstraZeneca, Bristol-Myers Squibb, KOS Pharmaceuticals Inc, Avant Immunotherapeutics, and Merck/Schering-Plough; served as a consultant for AstraZeneca, Reliant, Merck/Schering-Plough; participated on the speaker's bureau/received research grant support from Merck & Co Inc, Pfizer Inc, Novartis, AstraZeneca, and KOS Pharmaceuticals Inc; and received an honorarium from Merck & Co Inc, Merck/Schering-Plough, Pfizer Inc, Pharmacia, Novartis, AstraZeneca, Wyeth, and KOS Pharmaceuticals Inc. References 1. Backman JTKyrklund CNeuvonen MNeuvonen PJ Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther. 2002;72685- 691PubMedGoogle ScholarCrossref 2. Shek AFerrill MJ Statin-fibrate combination therapy. Ann Pharmacother. 2001;35908- 917PubMedGoogle ScholarCrossref 3. Ballantyne CMCorsini ADavidson MH et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med. 2003;163553- 564PubMedGoogle ScholarCrossref 4. Kyrklund CBackman JTKivisto KTNeuvonen MLaitila JNeuvonen PJ Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69340- 345PubMedGoogle ScholarCrossref 5. Pan WJGustavson LEAchari R et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000;40316- 323PubMedGoogle ScholarCrossref 6. Prueksaritanont TZhao JJMa B et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002;3011042- 1051PubMedGoogle ScholarCrossref 7. Prueksaritanont TTang CQiu YMu LSubramanian RLin JH Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;301280- 1287PubMedGoogle ScholarCrossref 8. Martin PDDane ALSchneck DWWarwick MJ An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther. 2003;25459- 471PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Possible Differences Between Fibrates in Pharmacokinetic Interactions With Statins

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Publisher
American Medical Association
Copyright
Copyright © 2003 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.163.19.2394
Publisher site
See Article on Publisher Site

Abstract

The combination of a fibric acid derivative (fibrate) and a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) may offer a therapeutic advantage to patients with combined hyperlipidemia who respond inadequately to either agent alone. However, physicians remain reluctant to prescribe statins and fibrates concomitantly because of their concern that drug-drug interactions will increase the probability of muscle damage. Fibrates have been shown to increase statin plasma concentrations and to be associated with an increased risk of severe myopathy and rhabdomyolysis when prescribed in combination with a statin.1,2 The question of whether the increase in risk is due to a class effect for all fibrate-statin combinations remains unanswered. In our review of the risk of myopathy with statin therapy, we presented information on fibrate-statin interactions.3 At the time of the writing of this article, several studies had shown that gemfibrozil use increases plasma concentration of statins.4 In contrast, use of fenofibrate—another commonly prescribed fibric acid derivative—did not appear to affect the plasma concentration of pravastatin.5 The mechanism of this differential interaction of fibrates on statin metabolism was not well understood. The recent identification of a major metabolic pathway for statins and findings from a new pharmacokinetic study provide important insight into the mechanism of the observed interaction between gemfibrozil and statins. Glucuronidation has recently been identified as a major pathway for statin clearance. It has been demonstrated that gemfibrozil inhibits glucuronidation, thereby increasing the concentration of the active statin acid.6 This inhibition is most marked with cerivastatin sodium, the statin associated with most reports of myopathy and rhabdomyolysis, which was withdrawn from the market in August 2001 because of concerns about adverse events. A new report by Prueksaritanont et al7 indicated that there might be potential differences between fibrates in their ability to affect the glucuronidation pathway. In this study, Prueksaritanont and colleagues assessed the effects of gemfibrozil and fenofibrate on statin metabolism in human hepatocytes. Gemfibrozil was not only found to moderately interact with the CYP3A4 pathway but was also found to be a strong inhibitor of the glucuronidation-mediated lactonization of several statins. In contrast, fenofibrate showed a minimal effect on all metabolic pathways, including the statin glucuronidation. These findings were confirmed in another study that examined the effect of the coadministration of fenofibrate with rosuvastatin calcium on pharmacokinetic properties of rosuvastatin, a new statin recently approved in the United States.8 No changes were observed in the pharmacokinetic properties of either agent when concomitantly administered. We believe that these data are important for understanding the drug interactions observed between statins and gemfibrozil and highlight the differences between the fibrates in their interaction with statin metabolism. The lack of observed metabolic interaction between fenofibrate and statins suggests that the fenofibrate-statin combination may be a safer treatment approach than the gemfibrozil-statin combination for cardiovascular risk reduction in patients with combined hyperlipidemia. Dr Ballantyne has received grant/research support from AstraZeneca, Merck & Co Inc, Pfizer Inc, Novartis, Reliant, Schering-Plough, GlaxoSmithKline, and diaDexus Inc; served as a consultant for AstraZeneca, Merck & Co Inc, Pfizer Inc, Novartis, Reliant, and Schering-Plough; and participated on the speaker's bureau for AstraZeneca, Merck & Co Inc, Pfizer Inc, Novartis, Reliant, Schering-Plough, KOS Pharmaceuticals Inc, Bristol-Myers Squibb and Sanofi-Synthelabo. Dr Davidson has received grant/research support from Merck & Co Inc, Pfizer Inc, AstraZeneca, Bristol-Myers Squibb, KOS Pharmaceuticals Inc, Avant Immunotherapeutics, and Merck/Schering-Plough; served as a consultant for AstraZeneca, Reliant, Merck/Schering-Plough; participated on the speaker's bureau/received research grant support from Merck & Co Inc, Pfizer Inc, Novartis, AstraZeneca, and KOS Pharmaceuticals Inc; and received an honorarium from Merck & Co Inc, Merck/Schering-Plough, Pfizer Inc, Pharmacia, Novartis, AstraZeneca, Wyeth, and KOS Pharmaceuticals Inc. References 1. Backman JTKyrklund CNeuvonen MNeuvonen PJ Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther. 2002;72685- 691PubMedGoogle ScholarCrossref 2. Shek AFerrill MJ Statin-fibrate combination therapy. Ann Pharmacother. 2001;35908- 917PubMedGoogle ScholarCrossref 3. Ballantyne CMCorsini ADavidson MH et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med. 2003;163553- 564PubMedGoogle ScholarCrossref 4. Kyrklund CBackman JTKivisto KTNeuvonen MLaitila JNeuvonen PJ Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69340- 345PubMedGoogle ScholarCrossref 5. Pan WJGustavson LEAchari R et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000;40316- 323PubMedGoogle ScholarCrossref 6. Prueksaritanont TZhao JJMa B et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002;3011042- 1051PubMedGoogle ScholarCrossref 7. Prueksaritanont TTang CQiu YMu LSubramanian RLin JH Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;301280- 1287PubMedGoogle ScholarCrossref 8. Martin PDDane ALSchneck DWWarwick MJ An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther. 2003;25459- 471PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Oct 27, 2003

Keywords: statins,fibric acid derivatives

References

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