Plasma concentrations of active simvastatin acid are increased by gemfibrozil

Background: Concomitant treatment with simvastatin and gemfibrozil, two lip id-lowering drugs, has been associated with occurrence of myopathy in case reports. The aim of this study was to determine whether gemfibrozil affects the pharmacokinetics of simvastatin and whether it affects CYP3A4 activity in vitro. Methods: A double-blind, randomized crossover study with two phases (placeb o and gemfibrozil) was carried out. Ten healthy volunteers were given gemfi brozil (600 mg twice daily) or placebo orally for 3 days. On day 3 they ing ested a single 40-mg dose of simvastatin, Plasma concentrations of simvasta tin and simvastatin acid were measured up to 12 hours. In addition, the eff ect of gemfibrozil (0 to 1200 mu mol/L) on midazolam 1'-hydroxylation, a CY P3A4 model reaction, was investigated in human liver microsomes in vitro. Results: Gemfibrozil increased the mean total area under the plasma concent ration-time curve of simvastatin [AUC(0-infinity)] by 35% (P <.01) and the AUC(0-infinity) of simvastatin acid by 185% (P <.001), The elimination half -life of simvastatin was increased by 74% (P <.05), and that of simvastatin acid was increased by 52% (P <.01) by gemfibrozil, The peak concentration of simvastatin acid was increased by 112%, from 3.20 +/- 2.73 ng/mL to 6.78 +/- 4.67 ng/mL (mean +/- SD; P <.01). In vitro, gemfibrozil showed no inhi bition of midazolam 1'-hydroxylation, Conclusions: Gemfibrozil increases plasma concentrations of simvastatin and , ia particular, its active form, simvastatin acid, suggesting that the inc reased risk of myopathy in combination treatment is, at least partially, of a pharmacokinetic origin. Because gemfibrozil does not inhibit CYP3A4 in v itro, the mechanism of the pharmacokinetic interaction is probably inhibiti on of non-CYP3A4-mediated metabolism of simvastatin acid.