Skip to main content
Log in

Pravastatin, an HMG-CoA Reductase Inhibitor, Is Transported by Rat Organic Anion Transporting Polypeptide, oatp2

Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. We previously demonstrated the HMG-CoA reductase inhibitor, pravastatin, is actively taken up into isolated rat hepatocytes through multispecific organic anion transporters. The present study examined whether a newly cloned organic anion transporting polypeptide (oatp2) transports pravastatin.

Methods. We investigated functional expression of oatp2 in Xenopus laevis oocytes, to examine [14C] pravastatin uptake.

Results. [14C] Pravastatin (30 μM) uptake into oatp2 cRNA-injected oocytes was 40 times higher than that of water-injected control oocytes. The oatp2-mediated pravastatin uptake was Na+-independent and saturable. The Michaelis-Menten constant was 37.5 ± 9.9 μM, a level comparable to that obtained in isolated rat hepatocytes in our previous study. As is the case with rat hepatocytes, the uptake of pravastatin (30 μM) was inhibited by 300 μM concentrations of taurocholate, cholate, bromosulfophthalein, estradiol-17β-glucuronide, and simvastatin acid, but not by para-aminohippurate. On the other hand, [14C] simvastatin acid (30 μM) uptake of oatp2 cRNA-injected oocytes was not significantly different from that of water-injected oocytes.

Conclusions. The cloned oatp2 was identified as the transporter responsible for the active hepatocellular pravastatin uptake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

REFERENCES

  1. S. M. Grundy. HMG-CoA reductase inhibitors for treatment of hyper-cholesterolemia. N. Engl. J. Med. 319:324–332 (1988).

    Google Scholar 

  2. D. R. Illingworth. HMG-CoA reductase inhibitors. Lipidology 2:244–34 (1991).

    Google Scholar 

  3. W. A. Scott, E. M. Mahoney, and S. T. Mosley. Mechanism of action and differential pharmacology of pravastatin, a hydrophilic and selective HMG-CoA reductase inhibitor. In J. C. LaRosa (eds.), New Advances in the Control of Lipid Metabolism: Focus on Pravastatin, Royal Society of Medicine, 1989, pp. 1–8.

  4. Y. Tsujita, M. Kuroda, Y. Shimada, K. Tanzawa, M. Arai, I. Kaneko, M. Tanaka, H. Masuda, C. Tamura, Y. Watanabe, and S. Fujii. CS-514, a competitive inhibitor of 3-hydroxyl-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim. Biophys. Acta 1045:115–120 (1990).

    Google Scholar 

  5. T. Koga, Y. Shimada, M. Kuroda, Y. Tsujita, K. Hasegawa, and M. Yamazaki. Tissue selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Biochim. Biophys. Acta 877: 50–60 (1986).

    Google Scholar 

  6. P. J. Meier. Transport polarity of hepatocytes. Semin. Liver Dis. 8:649–661 (1988).

    Google Scholar 

  7. T. Komai, E. Shigehara, T. Tokui, T. Koga, M. Ishigami, C. Kuroiwa, and S. Horiuchi. Carrier-mediated uptake of pravastatin by rat hepatocytes in primary culture. Biochem. Pharmacol. 43:667–670 (1992).

    Google Scholar 

  8. M. Yamazaki, H. Suzuki, M. Hanano, T. Tokui, T. Komai, and Y. Sugiyama. Na+-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. Am. J. Physiol. 264:G36–G44 (1993).

    Google Scholar 

  9. M. Yamazaki, T. Tokui, M. Ishigami, and Y. Sugiyama. Tissue-selective uptake of pravastatin in rats: contribution of a specific carrier-mediated uptake system. Biopharm. Drug Disposit. 17:990.1–15 (1996).

    Google Scholar 

  10. M. Ishigami, T. Tokui, T. Komai, K. Tsukahara, M. Yamazaki, and Y. Sugiyama. Evaluation of the uptake of pravastatin by perfused rat liver and primary cultured rat hepatocytes. Pharm. Res. 12:1741–1745 (1995).

    Google Scholar 

  11. M. Yamazaki, H. Suzuki, and Y. Sugiyama. Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharm. Res. 13:497–513 (1996).

    Google Scholar 

  12. E. Jacquemin, B. Hagenbuch, B. Stieger, A. W. Wolkoff, and P. J. Meier. Expression cloning of a rat liver Na+-independent organic anion transporter. Proc. Natl. Acad. Sci. USA 91:133–137 (1994).

    Google Scholar 

  13. A. J. Bergwerk, X. Shi, A. C. Ford, N. Kanai, E. Jacquemin, R. D. Burk, S. Bai, P. M. Novikoff, B. Stieger, P. J. Meier, V. L. Schuster, and A. W. Wolkoff. Immunologic distribution of an organic anion transport protein in rat liver and kidney. Am. J. Physiol. 271:G231–G238 (1996).

    Google Scholar 

  14. X. Bossuyt, M. Muller, B. Hagenbuch, and P. J. Meier. Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver. J. Pharmacol. Exp. Ther. 276:891–896 (1996).

    Google Scholar 

  15. U. Eckhardt, J. A. Horz, E. Petzinger, W. Stuber, M. Reers, G. Dickneite, H. Daniel, M. Wagener, B. Hagenbuch, B. Stieger, and P. J. Meier. The peptide-based thrombin inhibitor CRC 220 is a new substrate of basolateral rat liver organic anion transporting polypeptide. Hepatology 24:380–384 (1996).

    Google Scholar 

  16. H. Kouzuki, H. Suzuki, K. Ito, R. Ohashi, and Y. Sugiyama. Contribution of organic anion transporting polypeptide to the uptake of its possible substrates into rat hepatocytes. J. Pharmacol. Exp. Ther. in press.

  17. T. Abe, M. Kakyo, H. Sakagami, T. Tokui, T. Nishio, M. Tanemoto, H. Nomura, S. C. Hebert, S. Matsuno, H. Kondo, and H. Yawo. Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate, and comparison with oatp2. J. Biol. Chem. 273:22395–22401 (1998).

    Google Scholar 

  18. B. Noe, B. Hagenbuch, B. Stieger, and P. J. Meier. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc. Natl. Acad. Sci. 94:10346–10350 (1997).

    Google Scholar 

  19. M. Kakyo, H. Sakagami, T. Nishio, D. Nakai, R. Nakagomi, T. Tokui, T. Naitoh, S. Matsuno, T. Abe, and H. Yawo. Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2). FEBS Letter (in press).

  20. A. Goldin. Maintenance of Xenopus laevis and oocyte injection. Methods in Enzymology 207:266–279 (1992).

    Google Scholar 

  21. E. R. Liman, J. Tytgat, and P. Hess. Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs. Neuron 9:861–871 (1992).

    Google Scholar 

  22. T. Sekine, N. Watanabe, M. Hosoyamada, Y. Kanai, and H. Endou. Expression cloning and characterization of a novel multispecific organic anion transporter. J. Biol. Chem. 272:18526–18529 (1997).

    Google Scholar 

  23. T. Komai, K. Kawai, T. Tokui, Y. Tokui, C. Kuroiwa, E. Shigehara, and M. Tanaka. Disposition and metabolism of pravastatin sodium in rats, dogs and monkeys. Eur. J. Met. Pharmacokin. 17:103–113 (1992).

    Google Scholar 

  24. I. Tamai, H. Takanaga, H. Maeda, T. Ogihara, M. Yoneda, and A. Tsuji. Proton-cotransport of pravastatin across intestinal brush-border membrane. Pharm. Res. 12:1727–1732 (1995).

    Google Scholar 

  25. M. Yamazaki, S. Akiyama, K. Ni'inuma, R. Nishigaki, and Y. Sugiyama. Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter (cMOAT). Drug Metab. Disposit. 25:1123–1129 (1997).

    Google Scholar 

  26. K. Zieglar and W. Stunkel. Tissue-selective action of pravastatin due to hepatocellular uptake via a sodium-independent bile acid transporter. Biochim. Biophys. Acta 1139:203–209 (1992).

    Google Scholar 

  27. A. Saheki, T. Terasaki, I. Tamai, and A. Tsuji. In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm. Res. 11:305–311 (1994).

    Google Scholar 

  28. L. Li, T. K. Lee, P. J. Meier, and N. Ballatori. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. J. Biol. Chem. 273:16184–16191 (1998).

    Google Scholar 

  29. A. K. van Vliet, G. C. F. van Thiel, R. H. Huisman, H. Moshage, S. H. Yap, and L. H. Cohen. Different effects of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors on sterol synthesis in various human cell types. Biochim. Biophys. Acta 1254:105–111 (1995).

    Google Scholar 

  30. G. A. Kullak-Ublick, B. Hagenbuch, B. Stieger, A. W. Wolkoff, and P. J. Meier. Functional characterization of the basolateral rat liver organic anion transporting polypeptide. Hepatol. 20:411–416 (1994).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Takaaki Abe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tokui, T., Nakai, D., Nakagomi, R. et al. Pravastatin, an HMG-CoA Reductase Inhibitor, Is Transported by Rat Organic Anion Transporting Polypeptide, oatp2. Pharm Res 16, 904–908 (1999). https://doi.org/10.1023/A:1018838405987

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018838405987

Navigation