Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine

Clin Pharmacol Ther. 2004 Aug;76(2):167-77. doi: 10.1016/j.clpt.2004.03.010.


Background: Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open-label trial involving stable heart transplant recipients (> or =6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP-C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP-C was also examined.

Methods: Ten subjects were assessed while taking 10 mg rosuvastatin for 10 days; 5 of these were then assessed while taking 20 mg rosuvastatin for 10 days. Rosuvastatin steady-state area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] and maximum observed plasma concentration (Cmax) were compared with values in controls (historical data from 21 healthy volunteers taking 10 mg rosuvastatin). Rosuvastatin uptake by OATP-C-transfected Xenopus oocytes was also studied by use of radiolabeled rosuvastatin with and without cyclosporine.

Results: In transplant recipients taking 10 mg rosuvastatin, geometric mean values and percent coefficient of variation for steady-state AUC(0-24) and Cmax were 284 ng. h/mL (31.3%) and 48.7 ng/mL (47.2%), respectively. In controls, these values were 40.1 ng. h/mL (39.4%) and 4.58 ng/mL (46.9%), respectively. Compared with control values, AUC(0-24) and Cmax were increased 7.1-fold and 10.6-fold, respectively, in transplant recipients. In transplant recipients taking 20 mg rosuvastatin, these parameters increased less than dose-proportionally. Rosuvastatin had no effect on cyclosporine blood concentrations. The in vitro results demonstrate that rosuvastatin is a good substrate for OATP-C-mediated hepatic uptake (association constant, 8.5 +/- 1.1 micromol/L) and that cyclosporine is an effective inhibitor of this process (50% inhibition constant, 2.2 +/- 0.4 micromol/L when the rosuvastatin concentration was 5 micromol/L).

Conclusions: Rosuvastatin exposure was significantly increased in transplant recipients on an antirejection regimen including cyclosporine. Cyclosporine inhibition of OATP-C-mediated rosuvastatin hepatic uptake may be the mechanism of the drug-drug interaction. Coadministration of rosuvastatin with cyclosporine needs to be undertaken with caution.

Publication types

  • Clinical Trial
  • Comparative Study
  • Controlled Clinical Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Animals
  • Area Under Curve
  • Biological Availability
  • Cells, Cultured
  • Cyclosporine / administration & dosage*
  • Cyclosporine / blood
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Fluorobenzenes / administration & dosage*
  • Fluorobenzenes / pharmacokinetics*
  • Follow-Up Studies
  • Graft Rejection / prevention & control
  • Graft Survival
  • Heart Transplantation / immunology*
  • Heart Transplantation / methods
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
  • Male
  • Middle Aged
  • Oocytes / drug effects
  • Pyrimidines / administration & dosage*
  • Pyrimidines / pharmacokinetics*
  • Rosuvastatin Calcium
  • Sulfonamides / administration & dosage*
  • Sulfonamides / pharmacokinetics*
  • Transplantation Immunology
  • Treatment Outcome
  • Xenopus


  • Fluorobenzenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • Cyclosporine
  • Rosuvastatin Calcium