Archives of Pharmacal Research

, Volume 25, Issue 4, pp 397–415 | Cite as

Interactions of cationic drugs and cardiac glycosides at the hepatic uptake level: studies in the ratin vivo, isolated perfused rat liver, isolated rat hepatocytes and oocytes expressing oatp2

  • Dirk K. F. Meijer
  • Jessica E. van Montfoort
Research Articles Reviews


This paper deals with a crucial mechanism for interaction of basic drugs and cardiac glycosides at the hepatic uptake level. Available literature data is provided and new material is presented to picture the differential transport inhibition of bulky (type2) cationic drugs by a number of cardiac glycosides in rat liver. It is shown that the so called organic anion transporting peptide 2 (oatp2) is the likely interaction site: differential inhibition patterns as observed in oocytes expressing oatp2, could be clearly identified also in isolated rat hepatocytes, isolated perfused rat liver and the ratin vivo. The anticipation of transport interactions at the hepatic clearance level should be based on data on the relative affinities of interacting substrates for the transport systems involved along with knowledge on the pharmacokinetics of these agents as well as the chosen dose regimen in the studied species. This review highlights the importance of multispecific tranporter systems such as OATP, accommodating a broad spectrum of organic compounds of various charge, implying potential transport interactions that can affect body distribution and organ clearance.

Key words

Organic cations Cardiac glycosides Basic drugs Hepatic Uptake oatp2 Drug interactions Oubain K-Strophanthoside Digitoxin Rocuronium Curare-like agents 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Blom, A., Keulemans, K., and Meijer, D. K. F. Transport of dibromosulphthalein by isolated rat hepatocytes.Biochem. Pharmacol., 30, 1809–1816 (1981).PubMedCrossRefGoogle Scholar
  2. Blom, A., Scaf, A. H. J., and Meijer, D. K. F. Hepatic drug transport in the rat. A comparison between isolated hepatocytes, the isolated perfused liver and the liverin vivo.Biochem. Pharmacol., 31, 1553–1565 (1982).PubMedCrossRefGoogle Scholar
  3. Bossuyt, X., Müller, M., Hagenbuch, B., and Meier, P. J. Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver.J. Pharmacol. Exp. Ther., 276, 891–896 (1996a).PubMedGoogle Scholar
  4. Bossuyt, X., Müller, M., and Meier, P. J. Multispecific amphipathic substrate transport by an organic anion transporter of human liver.J. Hepatol., 25, 733–738 (1996b).PubMedCrossRefGoogle Scholar
  5. Braakman, I., Keij, J., Hardonk, M. J., Meijer, D. K. F., and Groothuis, G. M. M. Separation of periportal and perivenous rat hepatocytes by fluorescence-activated cell sorting: confirmation with colloidal gold as an exogenous marker.Hepatology (Philadelphia), 13, 73–82 (1991).Google Scholar
  6. Budiman, T., Bamberg, E., Koepsell, H., and Nagel, G. Mechanism of electrogenic cation transport by the cloned organic cation transporter 2 from rat.J. Biol. Chem., 275, 29413–29420(2000).PubMedCrossRefGoogle Scholar
  7. Burckhardt, G. and Wolff, N. A. Structure of renal organic anion and cation transporters.Am. J. Physiol., 278, F853-F866 (2000).Google Scholar
  8. Buscher, H.-P., Fricker, G., Gerok, W., Kramer, W., Kurz, G., Müller, M., and Schneider, S., Membrane transport of amphiphilic compounds by hepatocytes, In Greten, H., Windier, E., and Beisiegel, U. (Eds.).Receptor-Mediated Uptake in the Liver. Springer-Verlag-Berlin, Heidelberg, pp. 189–199,(1986).Google Scholar
  9. Buscher, H.-P., Gerok, W., Köllinger, M., Kurz, G., Müller, M., Nolte, A., and Schneider, S. Transport systems for amphipathic compounds in normal and neoplastic hepatocytes.Adv. Enzyme Regul., 27, 173–192 (1988).PubMedCrossRefGoogle Scholar
  10. Dresser, M. J., Leabman, M. K., and Giacomini, K. M. Transporters involved in the elimination of drugs in the kidney: Organic anion transporters and organic cation transporters.J. Pharm. Sci., 90, 397–421 (2001).PubMedCrossRefGoogle Scholar
  11. Groothuis, G. M. M., Meijer, D. K. F., and Hardonk, M. J. Morphological studies on selective acinar liver damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride.Naunyn-Schmiedeberg’s Arch. Pharmacol., 322, 298–309 (1983).CrossRefGoogle Scholar
  12. Hagenbuch, B., Scharschmidt, B. F., and Meier, R. J. Effect of antisense oligonucleotides on the expression of hepatocellular bile acid and organic anion uptake systems in Xenopus laevis oocytes.Biochem. J., 316, 901–904 (1996).PubMedGoogle Scholar
  13. Hedman, A. Inhibition by basic drugs of digoxin secretion into human bile.Eur. J. Clin. Pharmacol., 42, 457–459 (1992).PubMedCrossRefGoogle Scholar
  14. Hedman, A., Angelin, B., Arvidsson, A., Dahlqvist, R., and Nilsson, B. Interactions in the renal and biliary elimination of digoxin: Stereoselective difference between quinine and quinidine.Clin. Pharmacol. Ther. (St. Louis), 47, 20–26 (1990).Google Scholar
  15. Hedman, A. and Meijer, D. K. F. Stereoselective inhibition by the diastereomers quinidine and quinine of uptake of cardiac glycosides into isolated rat hepatocytes.J. Pharm. Sci., 87, 457–461 (1998a).PubMedCrossRefGoogle Scholar
  16. Hedman, A. and Meijer, D. K. F. The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides.J. Hepatol., 28, 240–249 (1998b).PubMedCrossRefGoogle Scholar
  17. Hooiveld, G. J. E. J., Heegsma, J., Van Montfoort, J. E., Jansen, P. L. M., Meijer, D. K. F., and Müller, M. Stereoselective transport of hydrophilic quaternary drugs by human MDR1 and rat Mdr1b P-glycoproteins.Br. J. Pharmacol., 135, 1685–1694(2002).PubMedCrossRefGoogle Scholar
  18. Hooiveld, G. J. E. J., Van Montfoort, J. E., Meijer, D. K. F., and Müller, M. Function and regulation of ATP-binding cassette transport proteins involved in hepatobiliary transport.Eur. J. Pharm. Sci., 12, 525–543 (2001).PubMedCrossRefGoogle Scholar
  19. Koepsell, H. Organic cation transporters in intestine, kidney, liver, and brain.Annu. Rev. Physiol., 60, 243–266 (1998).PubMedCrossRefGoogle Scholar
  20. Koepsell, H., Busch, A., Gorboulev, V., and Arndt, P. Structure and function of renal organic cation transporters.News Physiol. Sci., 13, 11–16 (1998).PubMedGoogle Scholar
  21. Koepsell, H., Gorboulev, V., and Arndt, P. Molecular pharmacology of organic cation transporters in kidney.J. Membr. Biol., 167, 103–117 (1999).PubMedCrossRefGoogle Scholar
  22. Kullak-Ublick, G.-A., Beuers, U., and Paumgartner, G. Hepatobiliary transport.J. Hepatol., 32, 3–18 (2000).PubMedCrossRefGoogle Scholar
  23. Kullak-Ublick, G.-A., Hagenbuch, B., Stieger, B., Schteingart, C. D., Hofmann, A. F., Wolkoff, A. W., and Meier, P. J. Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver.Gastro, 109, 1274–1282(1995).CrossRefGoogle Scholar
  24. Kullak-Ublick, G.-A., Hagenbuch, B., Stieger, B., Wolkoff, A. W., and Meier, P. J. Functional characterization of the basolateral rat liver organic anion transporting polypeptide.Hepatology (Philadelphia), 20, 411–416 (1994).Google Scholar
  25. Li, L. Q., Meier, P. J., and Ballatori, N. Oatp2 mediates bidirectional organic solute transport: A role for intracellular glutathione.Mol. Pharmacol., 58, 335–340 (2000).PubMedGoogle Scholar
  26. Meijer, D. K. F., Arends, J. W., and Weitering, J. G. The cardiac glycoside sensitive step in the hepatic transport of the bisquaternary ammonium compound, hexafluorenium.Eur. J. Pharmacol., 15, 245–251 (1971).PubMedCrossRefGoogle Scholar
  27. Meijer, D. K. F., Bos, E. S., and Van der Laan, K. J. Hepatic transport of mono and bisquaternary ammonium compounds.Eur. J. Pharmacol., 11, 371–377 (1970).PubMedCrossRefGoogle Scholar
  28. Meijer, D. K. F., Hooiveld, G. J. E. J., Schinkel, A. H., Van Montfoort, J. E., and Smit, J. W. Transport mechanisms for cationic drugs in liver, kidneys and intestine studied at the molecular level.Nova Acta Leopold., NF 78, 201–210 (1998).Google Scholar
  29. Meijer, D. K. F., Jansen, P. L. M., and Groothuis, G. M. M., Hepatobiliary disposition and targeting of drugs and genes, In Bircher, J., Benhamou, J.-P., Mclntyre, N., Rizzetto, M., and Rodés, J. (Eds.).Oxford Textbook of Clinical Hepatology, Second Edition. Oxford University Press, New York, pp. 87–144, (1999a).Google Scholar
  30. Meijer, D. K. F., Keulemans, K., and Mulder, G. J. Isolated perfused rat liver technique.Methods Enzymol., 77, 81–94 (1981).PubMedCrossRefGoogle Scholar
  31. Meijer, D. K. F., Mol, W. E. M., Müller, M., Steen, H., and Kurz, G., Carrier-mediated transport in the hepatic distribution and elimination of organic cations, In Bock, K. W., Matern, S., Gerok, W., and Schmid, R. (Eds.).Hepatic Metabolism and Disposition of Endo- and Xenobiotics. Kluwer Academic Publishers, Dordrecht, pp. 259–270, (1991).Google Scholar
  32. Meijer, D. K. F. and Nijssen, H. M. J., Transport of drugs, proteins and drug-protein conjugates, In Ballet, F. and Thurman, R. G. (Eds.).Research in Perfused Liver: Clinical and Basic Applications. INSERM/John Libbey, London, pp. 165–208,(1991).Google Scholar
  33. Meijer, D. K. F. and Scaf, A. H. J. Inhibition of the transport of d-tubocurarine from blood to bile by k-strophantoside in the isolated perfused rat liver.Eur. J. Pharmacol., 4, 343–346 (1968).CrossRefGoogle Scholar
  34. Meijer, D. K. F., Smit, J. W., Hooiveld, G. J. E. J., Van Montfoort, J. E., Jansen, P. L. M., and Müller, M., The molecular basis for hepatobiliary transport of organic cations and organic anions, In Amidon, G. L. and Sadée, W. (Eds.).Membrane Transporters as Drug Targets. Kluwer Academic/Plenum Publishers, New York, pp. 89–157, (1999b).Google Scholar
  35. Meijer, D. K. F., Smit, J. W., and Müller, M. Hepatobiliary elimination of cationic drugs: the role of P-glycoproteins and other ATP-dependent transporters.Adv. Drug Delivery Rev., 25, 159–200 (1997).CrossRefGoogle Scholar
  36. Meijer, D. K. F., Vonk, R. J., and Weitering, J. G. The influence of various bile salts and some cholephilic dyes on Na+, K+-and Mg2+-activated ATPase of rat liver in relation to cholestatic effects.Toxicol. Appl. Pharmacol., 43, 597–612 (1978).PubMedCrossRefGoogle Scholar
  37. Meijer, D. K. F. and Weitering, J. G. Curare-like agents: relation between lipid solubility and transport into bile in perfused rat liver.Eur. J. Pharmacol., 10, 283–289 (1970).PubMedCrossRefGoogle Scholar
  38. Meijer, D. K. F., Weitering, J. G., Vermeer, G. A., and Scaf, A. H. J. Comparative pharmacokinetics of d-tubocurarine and metocurine in man.Anesthesiology, 51, 402–407 (1979).PubMedCrossRefGoogle Scholar
  39. Meijer, D. K. F., Weitering, J. G., and Vonk, R. J. Hepatic uptake and biliary excretion of d-tubocurarine and trimethylcurarine in the ratin vivo and in isolated perfused rat livers.J. Pharmacol. Exp. Ther., 198, 229–239 (1976).PubMedGoogle Scholar
  40. Mol, W. E. M., Fokkema, G. N., Weert, B., and Meijer, D. K. F. Mechanisms for the hepatic uptake of organic cations. Studies with the muscle relaxant vecuronium in isolated rat hepatocytes.J. Pharmacol. Exp. Ther., 244, 268–275 (1988).PubMedGoogle Scholar
  41. Mulder, G. J., Scholtens, E., and Meijer, D. K. F. Collection of metabolites in bile and urine from the rat.Methods Enzymol., 77, 21–30(1981).PubMedCrossRefGoogle Scholar
  42. Müller, M., Ishikawa, T., Berger, U., Klünemann, C., Lucka, L., Schreyer, A., Kannicht, C., Reutter, W., Kurz, G., and Keppler, D. ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt.J. Biol. Chem., 266, 18920–18926 (1991).PubMedGoogle Scholar
  43. Müller, M., Mayer, R., Hero, U., and Keppler, D. ATP-dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P-glycoprotein.FEBS Lett., 343, 168–172 (1994).PubMedCrossRefGoogle Scholar
  44. Nagel, G., Volk, C., Friedrich, T., Ulzheimer, J. C., Bamberg, E., and Koepsell, H. A reevaluation of substrate specificity of the rat cation transporter rOCT1.J. Biol. Chem., 272, 31953–31956 (1997).PubMedCrossRefGoogle Scholar
  45. Neef, C., Keulemans, K. T. P., and Meijer, D. K. F. Hepatic uptake and biliary excretion of organic cations. II. The influence of ion pair formation.Biochem. Pharmacol., 33, 3991–4002 (1984).PubMedCrossRefGoogle Scholar
  46. Neef, C. and Meijer, D. K. F. Structure-pharmacokinetics relationship of quaternary ammonium compounds. Correlation of physicochemical and pharmacokinetic parameters.Naunyn-Schmiedeberg’s Arch. Pharmacol., 328, 111–118 (1984).CrossRefGoogle Scholar
  47. Noé, B., Hagenbuch, B., Stieger, B., and Meier, P. J. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain.Proc. Natl. Acad. Sci. USA, 94, 10346–10350 (1997).PubMedCrossRefGoogle Scholar
  48. Okudaira, K., Sawada, Y., Sugiyama, Y., Iga, T., and Hanano, M. Effects of basic drugs on the hepatic transport of cardiac glycosides in rats.Biochem. Pharmacol., 37, 2949–2955 (1988).PubMedCrossRefGoogle Scholar
  49. Okudaira, K., Yamazaki, M., Sawada, Y., Sugiyama, Y., Iga, T., and Hanano, M. Correlation between the inhibitory effects of basic drugs on the uptake of cardiac glycosides and taurocholate by isolated rat hepatocytes.Pharm. Res., 9, 1152–1156(1992).PubMedCrossRefGoogle Scholar
  50. Oude Elferink, R. P. J., Meijer, D. K. F., Kuipers, F., Jansen, P. L. M., Groen, A. K., and Groothuis, G. M. M. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport.Biochim. Biophys. Acta, 1241, 215–268 (1995).PubMedGoogle Scholar
  51. Petzinger, E. and Fischer, K. Transport functions of the liver. Lack of correlation between ouabain uptake and binding to (Na+ + K+)-ATPase.Biochim. Biophys. Acta, 815, 334–340 (1985).PubMedCrossRefGoogle Scholar
  52. Petzinger, E., Fischer, K., and Rasold, H., Role of the bile acid transport system in hepatocellular ouabain uptake, In Erdmann, E., Grieff, K., and Akou, J. C. (Eds.).Cardiac Glycosides 1785-1985. Biochemistry, Pharmcology, Clinical Relevance. Steinkopf Verlag, Darmstadt, pp. 297–304, (1986).Google Scholar
  53. Proost, J. H. and Meijer, D. K. F. MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring.Comput. Biol. Med., 22, 155–163(1992).PubMedCrossRefGoogle Scholar
  54. Proost, J. H., Roggeveld, J., Wierda, J. M. K. H., and Meijer, D. K. F. Relationship between chemical structure and physicochemical properties of series of bulky organic cations and their hepatic uptake and biliary excretion rates.J. Pharmacol. Exp. Ther., 282, 715–726 (1997).PubMedGoogle Scholar
  55. Reichel, C., Gao, B., Van Montfoort, J., Cattori, V., Rahner, C., Hagenbuch, B., Stieger, B., Kamisako, T., and Meier, P. J. Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver.Gastro, 117, 688–695 (1999).CrossRefGoogle Scholar
  56. Satlin, L. M., Amin, V., and Wolkoff, A. W. Organic anion transporting polypeptide mediates organic anion/HCO3-exchange.J. Biol. Chem., 272, 26340–26345 (1997).PubMedCrossRefGoogle Scholar
  57. Schwenk, M., Wiedmann, T., and Remmer, H. Uptake, accumulation and release of ouabain by isolated rat hepatocytes.Naunyn-Schmiedeberg’s Arch. Pharmacol., 316, 340–344 (1981).CrossRefGoogle Scholar
  58. Smit, J. W., Duin, E., Steen, H., Oosting, R., Roggeveld, J., and Meijer, D. K. F. Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level.Br. J. Pharmacol., 123, 361–370 (1998a).PubMedCrossRefGoogle Scholar
  59. Smit, J. W., Schinkel, A. H., Weert, B., and Meijer, D. K. F. Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted.Br. J. Pharmacol., 124, 416–424 (1998b).PubMedCrossRefGoogle Scholar
  60. Song, l.-S., Chung, S.-J., and Shim, C.-K. Contribution of ion pair complexation with bile salts to biliary excretion of organic cations in rats.Am. J. Physiol., 281, G515-G525 (2001).Google Scholar
  61. Stacey, N. H. and Klaassen, C. D. Uptake of ouabain by isolated hepatocytes from livers of developing rats.J. Pharmacol. Exp. Ther., 211, 360–363 (1979).PubMedGoogle Scholar
  62. Steen, H. and Meijer, D. K. F., Organic cations, In Siegers, C.-P. and Watkins, J. B., III (Eds.).Biliary Excretion of Drugs and other Chemicals. Gustav Fischer Verlag, Stuttgart, pp. 239–272,(1991).Google Scholar
  63. Steen, H., Merema, M., and Meijer, D. K. F. A multispecific uptake system for taurocholate, cardiac glycosides and cationic drugs in the liver.Biochem. Pharmacol., 44, 2323–2331 (1992).PubMedCrossRefGoogle Scholar
  64. Steen, H., Oosting, R., and Meijer, D. K. F. Mechanisms for the uptake of cationic drugs by the liver: A study with tributylmethylammonium (TBuMA).J. Pharmacol. Exp. Ther., 258, 537–543(1991).PubMedGoogle Scholar
  65. Sugiyama, D., Kusuhara, H., Shitara, Y., Abe, T., and Sugiyama, Y. Effect of 17β-estradiol-d-17β-glucuronide on the rat organic anion transporting polypeptide 2-mediated transport differs depending on substrates.Drug Metab. Dispos., 30, 220–223 (2002).PubMedCrossRefGoogle Scholar
  66. Suzuki, H. and Sugiyama, Y., Transporters for bile acids and organic anions, In Amidon, G. L. and Sadée, W. (Eds.).Membrane Transporters as Drug Targets. Kluwer Academic/Plenum Publishers, New York, pp. 387–439, (1999).Google Scholar
  67. Van Montfoort, J. E., Hagenbuch, B., Fattinger, K. E., Müller, M., Groothuis, G. M. M., Meijer, D. K. F., and Meier, P. J. Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations.J. Pharmacol. Exp. Ther., 291, 147–152 (1999).PubMedGoogle Scholar
  68. Van Montfoort, J. E., Müller, M., Groothuis, G. M. M., Meijer, D. K. F., Koepsell, H., and Meier, P. J. Comparison of “type I” and “type II” organic cation transport by organic cation transporters and organic anion-transporting polypeptides.J. Pharmacol. Exp. Ther., 298, 110–115 (2001).PubMedGoogle Scholar
  69. Vonk, R. J., Jekel, P. A., Meijer, D. K. F., and Hardonk, M. J. Transport of drugs in isolated hepatocytes. The influence of bile salts.Biochem. Pharmacol., 27, 397–405 (1978).PubMedCrossRefGoogle Scholar
  70. Zhang, L., Brett, C. M., and Giacomini, K. M. Role of organic cation transporters in drug absorption and elimination.Annu. Rev. Pharmacol. Toxicol., 38, 431–460 (1998).PubMedCrossRefGoogle Scholar
  71. Zhang, L., Gorset, W., Dresser, M. J., and Giacomini, K. M. The interaction of n-tetraalkylammonium compounds with a human organic cation transporter, hOCT1.J. Pharmacol. Exp. Ther., 288, 1192–1198 (1999).PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2002

Authors and Affiliations

  • Dirk K. F. Meijer
    • 1
  • Jessica E. van Montfoort
    • 1
  1. 1.Department of Pharmacokinetics and Drug DeliveryGroningen University Institute of Drug Exploration (GUIDE)GroningenThe Netherlands

Personalised recommendations