Effects of statins on the pharmacokinetics of midazolam in healthy volunteers.

Lipid-lowering agents, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), are widely used to prevent coronary artery disease and often coadministered with other drugs, but there is a possibility that they induce pharmacological interactions with concomitant drugs. The authors aimed to investigate whether statins have any influence on cytochrome P450 (CYP) 3A4 enzyme activity. Eleven healthy volunteers were enrolled and evaluated for the effects of statins on the pharmacokinetics of midazolam in an open-label, randomized, 3-way crossover trial with simvastatin 10 mg, atorvastatin 10 mg, and pitavastatin 2 mg. The statins had no effects on the pharmacokinetics of midazolam and its metabolite, 1'-hydroxymidazolam. Furthermore, the area under the concentration-time curve ratios for 1'-hydroxymidazolam/midazolam from 0 to 10 hours showed no significant differences among 3 statins (simvastatin: 0.32 +/- 0.09, atorvastatin: 0.31 +/- 0.09, and pitavastatin: 0.31 +/- 0.12). These data suggest that statins, at least at low doses used in the present study, do not affect CYP3A4 and can be used safely without influencing CAP3A4 enzyme activity.