Regular Article
Intestinal Absorption of HMG-CoA Reductase Inhibitor Pitavastatin Mediated by Organic Anion Transporting Polypeptide and P-Glycoprotein/Multidrug Resistance 1

https://doi.org/10.2133/dmpk.DMPK-10-RG-073Get rights and content

Summary:

The purpose of this study was to investigate the involvement of organic anion transporting polypeptide (OATP/Oatp) and P-glycoprotein (P-gp)/multidrug resistance 1 (MDR1/Mdr1) in intestinal absorption of pitavastatin. Pitavastatin was found to be a substrate for human OATP1A2, OATP2B1, and MDR1 and rat Oatp1a5, Oatp2b1, and Mdr1a in experiments using transporter-expressing Xenopus oocytes and LLC-PK1 cell systems. Naringin inhibited Oatp1a5- and Mdr1a-mediated transport of pitavastatin with IC 50 values of 18.5 and 541 μM, respectively. The difference in the IC 50 values of naringin for Oatp1a5 and Mdr1a-mediated pitavastatin transport may account for the complex concentrationdependent effect of naringin on the intestinal absorption of pitavastatin. Rat intestinal permeability of pitavastatin measured by the in situ closed-loop perfusion method was indeed significantly reduced by 200 μM naringin, but was significantly increased by 1000 μM naringin. Furthermore, the permeability was significantly increased by elacridar, a potent inhibitor of Mdr1, while the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Oatp1a5 and Mdr1a are both involved in intestinal absorption of pitavastatin. Our present results indicate that OATP/Oatp and MDR1/ Mdr1 play roles in the intestinal absorption of pitavastatin as influx and efflux transporters, respectively.

References (40)

  • Y.Y. Lau et al.

    Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems

    J. Pharmacol. Exp. Ther.

    (2006)
  • M. Hirano et al.

    Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans

    J. Pharmacol. Exp. Ther.

    (2004)
  • I. Yamada et al.

    Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: similarities and difference in the metabolism of pitavastatin in monkeys and humans

    Xenobiotica

    (2003)
  • M.J. García et al.

    Clinical pharmacokinetics of statins

    Methods Find. Exp. Clin. Pharmacol.

    (2003)
  • K. Kajinami et al.

    NK-104: a novel synthetic HMG-CoA reductase inhibitor

    Expert Opin. Investig. Drugs

    (2000)
  • I. Tamai et al.

    Proton-cotransport of pravastatin across intestinal brushborder membrane

    Pharm. Res.

    (1995)
  • D. Kobayashi et al.

    Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane

    J. Pharmacol. Exp. Ther.

    (2003)
  • T. Nozawa et al.

    Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human

    J. Pharmacol. Exp. Ther.

    (2004)
  • Y. Shirasaka et al.

    Intestinal absorption of HMG-CoA reductase inhibitor pravastatin mediated by organic anion transporting polypeptide

    Pharm. Res.

    (2010)
  • T. Maeda et al.

    Identification of influx transporter for the quinolone antibacterial agent levofloxacin

    Mol. Pharm.

    (2007)
  • Cited by (58)

    • Rat Kidney Slices for Evaluation of Apical Membrane Transporters in Proximal Tubular Cells

      2019, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      The protein content of cells was measured with a protein assay kit (Bio-Rad, Hercules, CA) using BSA as the reference protein. Transport studies using LLC-PK1-expressing human MDR1 or rat mdr1a cells were carried out as described in a previous report.16,17 The cells were cultured in Medium 199 containing 10% fetal bovine serum, 100 units/mL penicillin, 100 μg/mL streptomycin, and 500 μg/mL G418 at 37°C in an atmosphere of 5% CO2.

    • Myotoxicity of statins: Mechanism of action

      2017, Pharmacology and Therapeutics
    • The Proteome of Filter-Grown Caco-2 Cells with a Focus on Proteins Involved in Drug Disposition

      2016, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Previous studies indicate that the hepatic uptake of pitavastatin and many other statins is strongly dependent on several members of the OATP family, collectively accounting for 60%-90% of the hepatic uptake (Vildhede et al., unpublished data, 2015).69,85,86 An involvement of OATPs in the intestinal absorption of pitavastatin has also been suggested,87 but the extent to which absorptive—and exorptive—intestinal transporters contribute to the overall pitavastatin absorption in humans has not been quantified. Transport experiments in Caco-2 cells showed that OATP2B1 contributed between 60% and 70% of the total transport rate in the concentration range expected in the small intestine after standard clinical doses (1-4 mg).

    View all citing articles on Scopus
    View full text