This question has resulted in confusion for many clinicians and even patients.  One of the primary reasons for such uncertainty is inaccurate alerts warning clinicians about drug interactions between fibric acid derivatives (fibrates) and another medication at the time of prescribing, ordering and/or dispensing.  For example, many drug interaction programs combine both fibrates, gemfibrozil (Lopid) and fenofibrate (Antara, Fenoglide, Lipofen, Lofibra, Tricor, Triglide, Trilipix), together when analyzing for interactions with HMG CoA reductase inhibitor (statin) medications.  However, it is incorrect for these programs to do this as the drug interaction with statins is predominately with gemfibrozil, not fenofibrate.1-6  Combining these medications together for the purpose of assessing drug interactions not only results in confusion for clinicians, but may result in the inappropriate delay or discontinuation of needed medications.  

Why is the interaction between statins and fibrates so significant that it has resulted in this alert by many programs?
While most statins are metabolized by the cytochrome P450 (CYP) enzyme system, all statins also undergo some degree of glucuronidation (or phase II metabolism) in the body for the purpose of enhancing elimination into the bile and/or urine.7,8  In addition, statins also utilize many influx and efflux transporters for their distribution throughout the body.  Inhibition of any one or a combination of these pathways (phase I, phase II and/or transporters) can result in the accumulation of statin in the body thereby putting the patient at greater risk for the development of rhabdomyolysis and/or hepatotoxicity.9 While neither of the fibrates are inhibitors of any of the CYP450 enzymes used by statins currently on the market, gemfibrozil can inhibit glucuronidation and some of the transporters they do rely upon. 

If gemfibrozil is the drug of concern,  why are both gemfibrozil and fenofibrate included in this warning?
The exact reason is not completely known, but it likely stems from the drug interaction between gemfibrozil and cerivastatin (Baycol).  Cerivastatin is no longer on the market; when compared to other statins, the combination of gemfibrozil and cerivastatin was associated with a 10-fold greater risk for developing rhabdomyolysis.10  

Why was this interaction so much greater than with other statins?
Unlike the other statins, cerivastatin was metabolized by CYP2C8, CYP3A4, and glucuronidation via UDP-glucuronosyltransferase (UGT) 1A1 and 1A3.  Unfortunately, gemfibrozil is known to be an inhibitor of CYP2C8, UGT1A1 and UGT1A3, thereby significantly decreasing the metabolism of cerivastatin.8,11-13  As such, gemfibrozil was contraindicated with the use of cerivastatin.  Unfortunately, this warning was not sufficient to prevent this adverse drug event and thus cerivastatin was pulled from the market.  As a result, it is plausible that computer software was simply programmed to identify the drug interaction between statins and fibrates (i.e., both gemfibrozil and fenofibrate) without considering the true mechanism.  While the drug interaction and risk for rhabdomyolysis was greatest between gemfibrozil and cerivastatin, gemfibrozil was also associated with drug interactions and risk for rhabdomyolysis with other statins.9,10 

Therefore, the drug interaction between statins and fibrates occurs only with gemfibrozil.  However, it is important for clinicians to remember that while gemfibrozil can inhibit the glucuronidation and possibly the transport of some statins, the absolute rate for development of rhabdomyolysis is low at 17 cases per 1 million prescriptions.10  Regardless, additional monitoring and counseling is warranted especially with the use of gemfibrozil and high dose statins.

References:

1. Prueksaritanont T, Tang C, Qiu Y et al.  Effects of fibrates on metabolism of statins in human hepatocytes.  Drug Metab Dispos  2002;30:1280-7.
2. Bergman AJ, Murphy G, Burke J et al.  Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans.  J Clin Pharmacol  2004;44:1054-62.
3. Pan WJ, Gustavson LE, Achari R et al.  Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers.  J Clin Pharmacol  2000;40:316-23.
4. Backman JT, Kyrklund C, Kivisto KT et al.  Plasma concentrations of active simvastatin acid are increased by gemfibrozil.  Clin Pharmacol Ther  2000;68:122-9.
5. Kyrklund C, Backman JT, Kivisto KT et al.  Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate.  Clin Pharmacol Ther  2001;69:340-5.
6. Backman JT, Kryklund C, Neuvonen M et al.  Gemfibrozil greatly increases plasma concentrations of cerivastatin.  Clin Pharmacol Ther  2002;72:685-91.
7. Neuvonen PJ, Niemi M, Backman JT.  Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.  Clin Pharmacol Ther  2006;80:565-81.
8. Prueksaritanont T, Subramanian R, Fang X et al.  Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization.  Drug Metab Dispos  2002;30:505-12.
9. Jacobson TA.  Statin safety: lessons from new drug applications for marketed statins.  Am J Cardiol  2006;97:44C-51C.
10. Law M, Rudnicka AR.  Statin safety: a systematic review.  Am J Cardiol  2006;97:52C-60C.
11. Prueksaritanont T, Zhao JJ, Ma B et al.  Mechanistic studies on metabolic interactions between gemfibrozil and statins.  J Pharmacol Exp Ther  2002;301:1042-51.
12. Wang JS, Neuvonen M, Wen X et al.  Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes.  Drug Metab Dispos  2002;30:1352-6.
13. Ogilvie BW, Zhang D, Li W et al.  Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions.  Drug Metab Dispos  2006;34:191-7.

Fibrate, Fenofibrate, Gemfibrozil, Lopid, Tricor, Lofibra, Trilipix, Lipofen, Antara, Fenoglide, HMG CoA Reductase, Statins, Myositis, Rhabdomyolysis