Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate

Background: Concomitant use of fibrates with statins has been associated wi th an increased risk of myopathy, but the underlying mechanism of this adve rse reaction remains unclear. Our aim was to study the effects of bezafibra te and gemfibrozil on the pharmacokinetics of lovastatin. Methods: This was a randomized, double-blind, 3-phase crossover study. Elev en healthy volunteers took 400 mg/day bezafibrate, 1200 mg/day gemfibrozil, or placebo for 3 days. On day 3, each subject ingested a single 40 mg dose of lovastatin, Plasma concentrations of lovastatin, lovastatin acid, gemfi brozil, and bezafibrate were measured up to 24 hours. Results: Gemfibrozil markedly increased the plasma concentrations of lovast atin acid, without affecting those of the parent lovastatin compared with p lacebo. During the gemfibrozil phase, the mean area under the plasma concen tration-time curve from 0 to 24 hours [AUC(0-24)] of lovastatin acid was 28 0% (range, 131% to 1184%; P < .001) and the peak plasma concentration (C-ma x) was 280% (range, 123% to 1042%; P < .05) of the corresponding value duri ng the placebo phase. Bezafibrate had no statistically significant effect o n the AUC(0-24) or C-max of lovastatin or lovastatin acid compared with pla cebo. Conclusions: Gemfibrozil markedly increases plasma concentrations of lovast atin acid, but bezafibrate does not. The increased risk of myopathy observe d during concomitant treatment with statins and fibrates may be partially o f a pharmacokinetic origin, The risk of developing myopathy during concomit ant therapy with lovastatin and a fibrate may be smaller with bezafibrate t han with gemfibrozil.