Abstract
The role of the multispecific bile acid transporter for cardiac glycoside uptake is still controversial. This study was designed to examine the inhibitory effects of basic drugs (verapamil, dipyridamole, nifedipine, chlorpromazine, disopyramide, quinidine, propranolol, and lidocaine) on taurocholate uptake by isolated rat hepatocytes and to compare these effects with inhibition of ouabain uptake. Sodium-dependent taurocholate uptake was significantly reduced, to 50-70% of the control value, by 50 µM verapamil, dipyridamole, and nifedipine. Sodium-independent taurocholate uptake was more extensively inhibited, to 20-40%, by these basic drugs. The inhibition of ouabain uptake correlated better with sodium-independent taurocholate uptake (γ = 0.918) than with sodium-dependent taurocholate uptake (γ = 0.714). Taurocholate competitively inhibited ouabain uptake in the absence of sodium. These results indicate that the cardiac glycoside transport system is similar to the sodium-independent taurocholate transport system.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
G. Ejvinsson. Effect of quinidine on plasma concentration of digoxin. Br. Med. J. 1:279–280 (1978).
W. Doering. Quinidine-digoxin interaction. Pharmacokinetics, underlying mechanisms and clinical implications. N. Engl. J. Med. 301:400–404 (1979).
K. Shenck-Gustafsson and R. Dahlqvist. Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction. Br. J. Clin. Pharmacol. 11:181–186 (1981).
T. P. Gibson and H. A. Nelson. Digoxin alters quinidine and quinidine alters digoxin pharmacokinetics in dogs. J. Lab. Clin. Med. 95:417–428 (1980).
J. D. Geiger, G. Das, and S. S. Parmar. Digoxin-quinidine interaction in unanesthetized guinea pigs. Pharmacology 25:177–182 (1982).
E. B. Leahey, J. A. Reiffel, R. E. Drusin, R. H. Heissenbattel, W. P. Lovejoy, and J. T. Bigger. Interaction between quinidine and digoxin. JAMA 240:533–534 (1978).
J. Sato, Y. Sawada, T. Iga, and M. Hanano. Effect of quinidine on digoxin distribution and elimination in guinea pigs. J. Pharm. Sci. 77:1137–1141 (1983).
K. E. Pedersen, A. Dorph-Pedersen, S. Hvidt, N. E. Klitgaard, and F. Nielsen-Kudsk. Digoxin-verapamil interaction. Clin. Pharmacol. Ther. 30:311–316 (1981).
C. G. Belz, W. Doering, R. Munkes, and J. Matthews. Interactions between digoxin and calcium antagonists and antiarrhythmic drugs. Clin. Pharmacol. Ther. 33:410–417 (1983).
J. O. Moysey, N. S. Y. Jaggaarao, E. N. Grundy, and D. A. Chamberlain. Amiodarone increases plasma digoxin concentrations. Br. Med. J. 282:272 (1981).
K. Okudaira, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Effect of quinindine on the hepatic uptake of digoxin in guinea pigs. J. Pharmacobio-Dyn. 12:24–30 (1989).
K. Okudaira, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Effect of basic drugs on the hepatic transport of cardiac glycosides in rats. Biochem. Pharmacol. 37:2949–2955 (1988).
C. D. Klaassen, D. L. Eaton, and S. Z. Cagen. In J. W. Bridges and L. F. Chasseaud (eds.), Progress in Drug Metabolism, John Wiley, New York, 1981, Vol. 6, pp. 1–75.
D. L. Eaton and C. D. Klaassen. Carrier-mediated transport of ouabain in isolated rat hepatocytes. J. Pharmacol. Exp. Ther. 205:480–488 (1978).
L. R. Schwarz, R. Burr, M. Schwenk, E. Pfaff, and H. Greim. Uptake of taurocholic acid into isolated rat-liver cells. Eur. J. Biochem. 55:617–623 (1975).
M. S. Anwer and D. Hegner. Effect of Na+ on bile acid uptake by isolated rat hepatocytes. Evidence for a heterogeneous system. Hoppe-Seyler Z. Physiol. Chem. 359:181–192 (1978).
Z. Petzinger, K. Fischerk, and H. Fasold. In Cardiac Glykosides 1785–1985, Steinkopf Verlag, Darmstadt, 1986, pp. 297–304.
E. Petzinger and K. Fischer. Transport functions of the liver. Lack of correlation between hepatocellular ouabain uptake and binding to sodium-potassium ATPase. Biochim. Biophys. Acta 815:334–340 (1985).
M. Schwenk, T. Wiedmann, and H. Remmer. Uptake, accumulation and release of ouabain by isolated rat hepatocytes. Naunyn-Schmiedeberg Arch. Pharmacol. 316:340–344 (1981).
D. L. Eaton and J. A. Richards. Kinetic evaluation of carriermediated transport of ouabain and taurocholic acid in isolated rat hepatocytes. Evidence for independent transport system. Biochem. Pharmacol. 35:2721–2725 (1986).
M. Frimmer and K. Ziegler. The transport of bile acids in liver cells. Biochim. Biophys. Acta 947:75–99 (1988).
C. D. Klaassen. Independence of bile acid and ouabain hepatic uptake: Studies in the newborn rat. Proc. Soc. Exp. Biol. Med. 157:66 (1978).
M. N. Berry and D. S. Friend. High-yield preparation of isolated rat liver parenchymal cells. J. Cell. Biol. 43:506–520 (1969).
H. Baur, S. Kasperek, and E. Pfaff. Criteria of viability of isolated liver cells. Hoppe-Seyler Z. Physiol. Chem. 356:827–838 (1975).
K. Yamaoka, Y. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharmacobio-Dyn. 4:879–885 (1981).
D. K. F. Meijer, W. E. M. Mol, M. Müller, and G. Kutz. Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cations. J. Pharmacokin. Biopharm. 18:35–71 (1990).
B. Zimmerli, J. Valantians, and P. J. Meier. Multispecificity of Na+-dependent taurocholate uptake in basolateral (sinusoidal) rat liver plasma membrane vesicles. J. Pharmacol. Exp. Ther. 250:301–308 (1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Okudaira, K., Yamazaki, M., Sawada, Y. et al. 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). https://doi.org/10.1023/A:1015895520584
Issue Date:
DOI: https://doi.org/10.1023/A:1015895520584