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.
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
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
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
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
- Prueksaritanont T, Tang C, Qiu Y et al. Effects of fibrates on
metabolism of statins in human hepatocytes. Drug Metab Dispos
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.
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.
JT, Kyrklund C, Kivisto KT et al. Plasma concentrations of active
simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther
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.
JT, Kryklund C, Neuvonen M et al. Gemfibrozil greatly increases plasma
concentrations of cerivastatin. Clin Pharmacol Ther 2002;72:685-91.
PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs:
mechanisms and clinical relevance. Clin Pharmacol Ther
T, Subramanian R, Fang X et al. Glucuronidation of statins in animals
and humans: a novel mechanism of statin lactonization. Drug Metab
- Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 2006;97:44C-51C.
- Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006;97:52C-60C.
T, Zhao JJ, Ma B et al. Mechanistic studies on metabolic interactions
between gemfibrozil and statins. J Pharmacol Exp Ther
JS, Neuvonen M, Wen X et al. Gemfibrozil inhibits CYP2C8-mediated
cerivastatin metabolism in human liver microsomes. Drug Metab Dispos
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.