title: Simvastatin does not affect CYP3A activity, quantified by the erythromycin breath test and oral midazolam pharmacokinetics, in healthy male subjects.
abstract: 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.
authors.affiliation: Merck Research Laboratories, Blue Bell, Pennsylvania, USA.
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: J M
authors.initials: JM
authors.lastname: Vega
authors.forename: J D
authors.initials: JD
authors.lastname: Rogers
authors.forename: K
authors.initials: K
authors.lastname: Gagliano
authors.forename: H E
authors.initials: HE
authors.lastname: Greenberg
authors.forename: L
authors.initials: L
authors.lastname: Gillen
authors.forename: M J
authors.initials: MJ
authors.lastname: Brucker
authors.forename: D
authors.initials: D
authors.lastname: McLoughlin
authors.forename: P H
authors.initials: PH
authors.lastname: Wong
authors.forename: S A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004917:Erythromycin / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D019821:Simvastatin / Q000494:pharmacology*; D016037:Single-Blind Method
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004917:Erythromycin; D019821:Simvastatin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam