Pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in rat

Xenobiotica. 2002 Aug;32(8):715-27. doi: 10.1080/00498250210144820.

Abstract

1. The pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, were investigated following single administration of (14)C-rosuvastatin in the Sprague-Dawley rat. 2. Following oral administration of (14)C-rosuvastatin at 1, 5 and 25 mg kg(-1), the C(max) and AUC of the radioactivity in the plasma increased more than the increase in dose ratio. 3. Excretion of radioactivity was 98.0% of the dose in the faeces and 0.4% in the urine up to 168 h after oral administration in the intact rat, and was 55.1% in the bile and 0.5% in the urine up to 48 h post-dosing in the bile duct-cannulated rat. The unchanged compound mainly accounted for the radioactivity in the bile and faeces. 4. In the tissue distribution study, the concentration of the radioactivity in the liver was markedly higher than those in the other tissues, and the radioactivity concentration ratios of the liver to the plasma were between 8 and 25 up to 48 h after oral administration. The liver-specific distribution of rosuvastatin was similarly recognized in whole-body autoradiography. 5. Metabolic profiling studies indicated that rosuvastatin would not be metabolized by CYP enzymes. 6. These results clarified that rosuvastatin selectively distributed in the liver - the target organ - and was excreted in the bile mainly as the unchanged compound.

MeSH terms

  • Animals
  • Area Under Curve
  • Bile / metabolism
  • Carbon Radioisotopes / pharmacokinetics
  • Female
  • Fluorobenzenes / pharmacokinetics*
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Male
  • Models, Chemical
  • Pyrimidines*
  • Rats
  • Rats, Sprague-Dawley
  • Rosuvastatin Calcium
  • Sulfonamides*
  • Time Factors
  • Tissue Distribution

Substances

  • Carbon Radioisotopes
  • Fluorobenzenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • Rosuvastatin Calcium
  • Hydroxymethylglutaryl CoA Reductases