Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro

Anaesthesia. 2005 Aug;60(8):747-53. doi: 10.1111/j.1365-2044.2005.04110.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atorvastatin
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / physiology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fluvastatin
  • Heptanoic Acids / pharmacology*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hypnotics and Sedatives / pharmacokinetics
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Microsomes, Liver / metabolism
  • Midazolam / pharmacokinetics*
  • Pyrroles / pharmacology*

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Fatty Acids, Monounsaturated
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypnotics and Sedatives
  • Indoles
  • Pyrroles
  • Fluvastatin
  • Cytochrome P-450 Enzyme System
  • Atorvastatin
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Midazolam