Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro.
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.
Mc Donnell
C G
CG
Department of Anaesthesia and Intensive Care Medicine, University College Cork, Ireland. conormcdonnell@hotmail.com
Shorten
G
G
Van Pelt
F N A M
FN
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*
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