Effects of gemfibrozil and rifampicin on the pharmacokinetics of HMG-CoA reductase inhibitors
Year: 2004
Type: dissertation
Study design: Clinical Trial
Abstract: HMG-CoA reductase inhibitors (statins) and fibrates are cholesterol-lowering drugs with complementary effects on plasma lipid levels.Although the combination of statins and fibrates is highly effective and listed in guidelines as an option in selected patient populations, it is also associated with a higher risk of severe muscle adverse effects.The risk for muscle adverse effects is known to increase with increasing statin concentrations.We carried out a series of investigations to determine whether the fibrate gemfibrozil increases plasma concentrations of four statins: simvastatin, lovastatin, cerivastatin and pravastatin.We also studied the effect of bezafibrate on lovastatin concentrations.Secondly, we studied the effects of antimicrobal drug rifampicin on the pharmacokinetics of simvastatin and pravastatin.Rifampicin is a model inducer of drug metabolism and drug transport.All the studies were randomised, blinded and placebo-controlled, with a cross-over design in healthy human volunteers.Pretreatment with clinically relevant doses of a fibrate or rifampicin was followed by a single dose of statin, whereafter blood samples were collected to determine the plasma statin concentrations, and the pharmacokinetic parameters calculated.Gemfibrozil significantly increased the area under the plasma concentration-curve (AUC) of all statins studied.On average, the AUC of cerivastatin, lovastatin acid, simvastatin acid, and pravastatin increased about six-fold, three-fold, three-fold and two-fold, compared to control phase values.The extent of the interactions comprised large interindividual variations, and the greatest increase in AUC by gemfibrozil was more than 10-fold for lovastatin acid and cerivastatin.Bezafibrate on the other hand, did not significantly affect the pharmacokinetics of lovastatin.Rifampicin reduced the AUC of active simvastatin acid to less than 10% of control phase values, whereas the mean AUC values of pravastatin decreased only to about 70%.These studies reveal a clinically significant pharmacokinetic drug interaction between gemfibrozil and statins.The adverse effects of the gemfibrozil-statin combinations may at least partially result from the pharmacokinetic interaction observed, and should be taken into account when choosing an appropriate combination and dosage of a statin and fibrate.Other commonly used fibrates may be void of the pharmacokinetic interaction with statins.The interaction between simvastatin and rifampicin is significant and may result in reduced statin efficacy, whereas the effect of rifampicin on pravastatin is considerably smaller.Therefore pravastatin could be used in preference to simvastatin in patients using potent inducers of CYP3A4.
Source: Työväentutkimus Vuosikirja
Author: Carl Kyrklund
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2552381401