title: Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro.
abstract: We have investigated the effects of the statins atorvastatin and fluvastatin on the cytochrome P450 3A4 enzyme (CYP 3A4)-mediated metabolism of midazolam in vitro, using pooled human liver microsomes. Midazolam was metabolised by human hepatic microsomes with a Michaelis-Menten constant (K(m)) of 5.25 (SD 1.2) micromol.l(-1). Atorvastatin was a moderate competitive inhibitor of CYP 3A4 with an inhibitory constant (K(i)) of 12.4 (95% CI 4.65-20.06) micromol.l(-1). Fluvastatin was a weak non-competitive inhibitor of CYP 3A4 with a K(i) of 94.3 (95% CI 55.01-133.5) micromol.l(-1). Both atorvastatin and fluvastatin inhibit the CYP 3A4-mediated metabolism of midazolam in vitro.
authors: Department of Anaesthesia and Intensive Care Medicine, University College Cork, Ireland. conormcdonnell@hotmail.com
authors: C G
authors: CG
authors: Mc Donnell
authors: G
authors: G
authors: Shorten
authors: F N A M
authors: FN
authors: Van Pelt
mesh_terms: D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006993:Hypnotics and Sedatives; D007211:Indoles; D011758:Pyrroles; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam