["Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin.", 'Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined.', 'In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2 were increased threefold (p < 0.001). In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by itraconazole. There were no differences in the serum concentrations of itraconazole and hydroxyitraconazole between studies I and II.'] Is simvastatin but not pravastatin very susceptible to interaction with the CYP3A4 inhibitor itraconazole?