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

Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-m...

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Published inJournal of clinical pharmacology Vol. 40; no. 11; p. 1274
Main Authors Prueksaritanont, T, Vega, J M, Rogers, J D, Gagliano, K, Greenberg, H E, Gillen, L, Brucker, M J, McLoughlin, D, Wong, P H, Waldman, S A
Format Journal Article
LanguageEnglish
Published England 01.11.2000
Subjects
Administration, Oral
Adult
Aryl Hydrocarbon Hydroxylases
Breath Tests
Cross-Over Studies
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Erythromycin - pharmacokinetics
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Male
Midazolam - pharmacokinetics
Oxidoreductases, N-Demethylating - antagonists & inhibitors
Simvastatin - pharmacology
Single-Blind Method
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Summary:Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.
ISSN:0091-2700
DOI:10.1177/009127000004001112