Browse > Article

Interactions of Cationic Drugs and Cardiac Glycosides at the Hepatic Uptake Level: Studies in the Rat in Vivo, Isolated Perfused Rat Liver, Isolated Rat Hepatocytes and Oocytes Expressing oatp2  

Dirk K.F.Meijer (Department of Pharmacokinetics and Drug Delivery, Groningen University Institute of Drug Exploration (GUIDE)Groningen, The Netherlands)
Jessica E.van Montfoort (Department of Pharmacokinetics and Drug Delivery, Groningen University Institute of Drug Exploration (GUIDE)Groningen, The Netherlands)
Publication Information
Archives of Pharmacal Research / v.25, no.4, 2002 , pp. 397-415 More about this Journal
Abstract
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 rat in 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.
Keywords
Organic cations; Cardiac glycosides; Basic drugs; Hepatic Uptake; oatp2; Drug interactions; Oubain; K-Strophanthoside; Digitoxin; Rocuronium;
Citations & Related Records

Times Cited By Web Of Science : 4  (Related Records In Web of Science)
Times Cited By SCOPUS : 4
연도 인용수 순위
1 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)   PUBMED
2 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. Hepatolagy (Philadelphia), 13, 73-82 (1991)
3 Burckhardt, G. and Wolff, N. A. Structure of renal organic anion and cation transporters. Am. J. Physiol., 278, F853-F866 (2000)
4 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)   DOI   ScienceOn
5 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. (Sf. Louis), 47, 20-26 (1990)   DOI   ScienceOn
6 Koepsell, H., Busch, A., Gorboulev, V., and Arndt, P. Structure and function of renal organic cation transporters. News Physiol. Sci., 13, 11-16 (1998)   PUBMED
7 Li, L. Q., Meier, P. J., and Ballatori, N. Oatp2 mediatesbidirectional organic solute transport: A role for intracellular glutathione. Mol. Pharmacol., 58, 335-340(2000)   PUBMED
8 Meijer, D. K. F., Arends, J. W, and Weltering, J. G. The cardiac glycoside sensitive step in the hepatic transport of the bisquaternary ammonium compound, hexafluorenium. Eur. J. Pharmacol., 15, 245-251 (1971)   DOI   ScienceOn
9 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)
10 Muller, 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)   DOI   ScienceOn
11 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)   DOI   PUBMED   ScienceOn
12 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)   PUBMED
13 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)   DOI   ScienceOn
14 Sugiyama, D., Kusuhara, H., Shitara, Y., Abe, T., and Sugiyama, Y. Effect of 17$\beta$-estradiol-d-17$\beta$-glucuronide on the rat organic anion transporting polypeptide 2-mediated transport differs depending on substrates. Drug Metab. Dispos., 30, 220-223 (2002)   DOI   ScienceOn
15 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)   DOI   ScienceOn
16 Smit, J. W., Schinkel, A. H., Weert, B., and Meijer, D. K. F. Hspatoblliary 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)   DOI   ScienceOn
17 Song, I.-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)
18 Muller, M., Ishikawa, T., Berger, U., Klunemann, 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)   PUBMED
19 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)   DOI   ScienceOn
20 Koepsell, H. Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol., 60, 243-266 (1998)   DOI   PUBMED   ScienceOn
21 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)   DOI   ScienceOn
22 Bossuyt, X., Muller, M., Hagenbuch, B., and Meier, P. J. Polyspecific drug and steroid clearance by an oganic anion transporter of mammalian liver. J. Pharmacal. Exp. Ther., 276, 891-896 (1996a)
23 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)   DOI   PUBMED   ScienceOn
24 Suzuki, H. and Sugiyama, Y., Transporters for bile acids and organic anions, In Amidon, G. L. and Sadee, W. (Eds.). Membrane Transporters as Drug Targets. Kluwer Academic/Plenum Publishers, New York, pp. 387-439, (1999)
25 Van Montfoort, J. E., Hagenbuch, B., Fattinger, K. E., Muller, 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)   PUBMED
26 Buscher, H.-P., Gerok, W, Kollinger, M., Kurz, G., Muller, M., Nolte, A., and Schneider, S. Transport systems for a amphipathic compounds in normal and neoplastic nepatocytes. Adv. Enzyme Regul., 27, 173-192 (1988)
27 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., Mcintyre, N., Rizzetto, M.,and Rodes, J. (Eds.). Oxford Textbook of Clinical Hepatology, Second Edition. Oxford University Press, New York, pp. 87-144,(1999a)
28 Van Montfoort, J. E., Muller, 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)   PUBMED
29 Hedman, A. Inhibition by basic drugs of digoxin secretion into human bile. Eur. J. Clin. Pharmacol., 42, 457-459 (1992)   PUBMED
30 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)   DOI   ScienceOn
31 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)
32 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)   DOI   ScienceOn
33 Hooiveld, G. J. E. J., Van Montfoort, J. E., Meijer, D. K. F., and Muller, M. Function and regulation of ATP-binding cassett transport proteins involved in hepatobiliary transport. Eur. J. Pharm. Sci., 12, 525-543 (2001)   DOI   ScienceOn
34 Meijer, D. K. F., Weitering, J. G., and Vonk, R. J. Hepatic uptake and biliary excretion of d-tubocurarine and trimethylcurarine in the rat in vivo and in isolated perfused rat livers. J. Pharmacol. Exp. Ther., 198, 229-239 (1976)   PUBMED
35 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)   DOI   PUBMED   ScienceOn
36 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)   DOI   PUBMED
37 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)   PUBMED
38 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 $Mg^{2+}-$activated ATPase of rat liver in relation to cholestatic effects. Toxicol. Appl. Pharmacol., 43, 597-612 (1978)   DOI   ScienceOn
39 Buscher, H.-P., Fricker, G., Gerok, W., Kramer, W., Kurz, G.,Muller, M., and Schneider, S., Membrane transport of a amphiphilic compounds by hepatocytes, In Greten, H., Windler, E., and Beisiegel, U. (Eds.). Receptor-Mediated Uptake in theLiver. Springer-Verlag-Berlin, Heidelberg, pp.189-199, (1986)
40 Koepsell, H., Gorboulev, V., and Arndt, P. Molecular pharmacology of organic cation transporters in kidney. J. Membr. BioI., 167, 103-117 (1999)   DOI   ScienceOn
41 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)   DOI   ScienceOn
42 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)   PUBMED
43 Meijer, D. K. F., Mol, W. E. M., Muller, 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)
44 Blom, A., Keulemans, K., and Meijer, D. K. F. Transport of dibromosuphthalein by isolated rat hepatocytes. Biachem. Pharmacol., 30, 1809-1816 (1981)   DOI   ScienceOn
45 Meijer, D. K. F., Smit, J. W., Hooiveld, G. J. E. J., Van Montfoort, J. E., Jansen, P. L. M., and Muller, M., The molecular basis for hepatobiliary transport of organic cations and organic anions, In Amidon, G. L. and Sadee, W. (Eds.). Membrane Transporters as Drug Targets. Kluwer Academic/Plenum Publishers, New York, pp. 89-157, (1999b)
46 Meijer, D. K. F. and Scaf, A. H. J. Inhibition of the transport of dtubocurarine from blood to bile by k-strophantoside in the isolated perfused rat liver. Eur. J. Pharmacol., 4, 343-346 (1968)   DOI   ScienceOn
47 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)   DOI   ScienceOn
48 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)   DOI   ScienceOn
49 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)
50 Meijer, D. K. F., Keulemans, K., and Mulder, G. J. Isolated perfused rat liver technique. Methods Enzymol., 77, 81-94 (1981)   DOI   PUBMED
51 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)   DOI   PUBMED   ScienceOn
52 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)
53 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)   DOI   ScienceOn
54 Hagenbuch, B., Scharschmidt, B. F., and Meier, P. 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)   DOI   PUBMED
55 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 liver in vivo. Biachem. Pharmacol., 31, 1553-1565 (1982)   DOI   ScienceOn
56 Bossuyt, X., Muller, M., and Meier, P. J. Multispecific amphipathic substrate transport by an organic anion transporter of human liver. J. Hepatol., 25, 733-738(1996b)   DOI   ScienceOn
57 Kullak-Ublick, G.-A, Beuers, U., and Paumgartner, G. Hepatobiliary transport. J. Hepatol., 32, 3-18 (2000)   PUBMED
58 Meijer, D. K. F., Smit, J. W, and Muller, M. Hepatobiliary elimination of cationic drugs: the role of P-glycoproteins and other ATP-dependent transporters. Adv. Drug Delivery Rev., 25, 159-200 (1997)   DOI   ScienceOn
59 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 Ievel. Br. J. Pharmacol., 123, 361-370 (1998a)   DOI   ScienceOn
60 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)   DOI   ScienceOn
61 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)   DOI   ScienceOn
62 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)   DOI   ScienceOn
63 Satlin, L. M., Amin, V., and Wolkoff, A. W. Organic anion transporting polypeptide mediates organic anion/$HCO_3-$ exchange. J. Biol. Chem., 272, 26340-26345 (1997)   DOI   ScienceOn
64 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)   DOI   ScienceOn
65 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)   DOI   ScienceOn
66 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)   PUBMED
67 Noe, 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)   DOI   ScienceOn
68 Petzinger, E., Fischer, K., and Fasold, 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)
69 Hooiveld, G. J. E. J., Heegsma, J., Van Montfoort, J. E., Jansen, P. L. M., Meijer, D.K. F., and Muller, M. Stereoselective transport of hydrophilic quaternary drugs by human MDR1 and rat Mdr1b P-glycoproteins. Br. J. Pharmacol., 135, 1685-1694 (2002)   DOI   ScienceOn
70 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)   DOI   ScienceOn
71 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)