The effect of gemfibrozil on the pharmacokinetics of rosuvastatin

Clin Pharmacol Ther. 2004 May;75(5):455-63. doi: 10.1016/j.clpt.2003.12.014.


Background: Coadministration of statins and gemfibrozil is associated with an increased risk for myopathy, which may be due in part to a pharmacokinetic interaction. Therefore the effect of gemfibrozil on rosuvastatin pharmacokinetics was assessed in healthy volunteers. Rosuvastatin has been shown to be a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. The effect of gemfibrozil on rosuvastatin uptake by cells expressing OATP2 was also examined.

Methods: In a randomized, double-blind, 2-period crossover trial, 20 healthy volunteers were given oral doses of gemfibrozil, 600 mg, or placebo twice daily for 7 days. On the fourth morning of each dosing period, a single oral dose of rosuvastatin, 80 mg, was coadministered. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin-lactone were measured. In addition, the effect of gemfibrozil on the uptake of radiolabeled rosuvastatin by OATP2-transfected Xenopus oocytes was studied.

Results: Gemfibrozil increased the rosuvastatin area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration [AUC(0-t)] 1.88-fold (90% confidence interval, 1.60-2.21) and the maximum observed rosuvastatin plasma concentration (C(max)) 2.21-fold (90% confidence interval, 1.81-2.69) compared with placebo. N-desmethyl rosuvastatin AUC(0-t) and C(max) decreased by 48% and 39%, respectively. Pharmacokinetics of rosuvastatin-lactone was unchanged. The in vitro results indicate that the maximum gemfibrozil inhibition of rosuvastatin OATP2-mediated uptake was 50%; the inhibition constant for the inhibitory process was 4.0 +/- 1.3 micromol/L.

Conclusions: Gemfibrozil increased rosuvastatin plasma concentrations approximately 2-fold, which is similar to the effect of gemfibrozil on pravastatin, simvastatin acid, and lovastatin acid plasma concentrations and substantially less than the effect observed for cerivastatin. Gemfibrozil inhibition of OATP2-mediated rosuvastatin hepatic uptake may contribute to the mechanism of the drug-drug interaction. Care is warranted when gemfibrozil is coadministered with rosuvastatin and other statins.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Animals
  • Area Under Curve
  • Cell Line / drug effects
  • Cell Line / metabolism
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Fluorobenzenes / administration & dosage
  • Fluorobenzenes / pharmacokinetics*
  • Gemfibrozil / administration & dosage
  • Gemfibrozil / pharmacology*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Hypolipidemic Agents / administration & dosage
  • Hypolipidemic Agents / pharmacology*
  • Male
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Organic Anion Transporters / metabolism
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacokinetics*
  • Reference Values
  • Rosuvastatin Calcium
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacokinetics*
  • Xenopus


  • Fluorobenzenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypolipidemic Agents
  • Organic Anion Transporters
  • Pyrimidines
  • Sulfonamides
  • Rosuvastatin Calcium
  • Gemfibrozil