Metabolic stability and uptake by human hepatocytes of pitavastatin, a new inhibitor of HMG-CoA reductase

Arzneimittelforschung. 2004;54(7):382-8. doi: 10.1055/s-0031-1296988.


To gain a better understanding of the metabolic stability and transport of pitavastatin (CAS 147526-32-7), a new and potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, experiments were conducted using human hepatocytes and oocytes of Xenopus laevis expressing human organic anion transporting polypeptide-2 (OATP2), respectively. Almost the entire radioactivity was from the unchanged substance or lactone form in human hepatocytes, and the cytochrome P450 (CYP)-mediated metabolism of pitavastatin was negligible. The results suggested that CYPs are not critically involved in determining the metabolic fate of pitavastatin. The hepatic uptake of pitavastatin reached saturation with a Km of 2.99 +/- 0.79 micromol/L. Also, the uptake of pitavastatin was mediated by OATP2 expressed in oocytes with a Km of 5.53 +/- 1.70 micromol/L. These results indicated that OATP2 plays a major role in the distribution of pitavastatin in liver. Furthermore, to elucidate the increase in the plasma concentration of pitavastatin in a clinical setting, the inhibitory effect of ciclosporin (cyclosporin A, CAS 59865-13-3) on the uptake of pitavastatin was examined. The uptake of pitavastatin was inhibited in the presence of cyclosporin A and the apparent IC50 value was 2.91 +/- 0.78 micromol/L. This result may at least partly explain the drug-drug interaction between pitavastatin and cyclosporin A. In conclusion, the characterization of transporters needs to be taken into account to avoid transporter-mediated drug-drug interaction.

MeSH terms

  • Animals
  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Cryopreservation
  • Cyclosporine / pharmacology
  • Estradiol / metabolism
  • Female
  • Hepatocytes / metabolism*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Indicators and Reagents
  • Kinetics
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Quinolines / antagonists & inhibitors
  • Quinolines / pharmacokinetics*
  • Xenopus laevis


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indicators and Reagents
  • Liver-Specific Organic Anion Transporter 1
  • Quinolines
  • Estradiol
  • Cyclosporine
  • pitavastatin