Simvastatin does not affect CYP3A activity, quantified by the erythromycinbreath test and oral midazolam pharmacokinetics, in healthy male subjects

Potential for inhibition of CYP3A activity by simvastatin, an MMG-CoA reduc tase inhibitor was evaluated in 12 healthy male subjects who received place bo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 mu Ci [C-14 N-met hyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent C-14 exhaled during the first hour (for EBT) and the pharmacokinetic parameters of mida zolam (AUC, C-max t(1/2)) were not affected following multiple once-daily o ral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.1 8 for EBT and 0.99 to 1.23 for midazolam AUG. In addition, the total urinar y recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjuga te) obtained from both treatments were not statistically different (p > 0.2 00). These data demonstrate that multiple dosing of simvastatin, at the hig hest recommended clinical dose, does not significantly alter the in vivo he patic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes. (C) 2000 the American College of Clinical Pharma cology.