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Kinetic analysis of the dose-dependent hepatic handling of 1-anilino-8-naphthalene sulfonate in rats

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Abstract

The dose dependency in the hepatic transport of an anionic fluorescent dye, 1-anilino-8-naphthalene sulfonate (ANS), was investigated by measuring the plasma disappearance and biliary excretion in rats. Bulk of the administered ANS distributed into the liver at 10 min after iv bolus injection. The plasma disappearance curves of ANS were then kinetically analyzed based on a two-compartment model, in which the ligand is eliminated only from the peripheral compartment (liver compartment). The total body clearance (CLtot) decreased with increasing dose of ANS. That is, the values of CLtot were 4.06 and 1.98 ml/min/per kg at the doses of 3 and 100 Μmol/kg, respectively. The clearances of the uptake and sequestration processes (CLup and CLseq, respectively) for a total ligand were constant irrespective of dose, while the efflux clearance (CLeff) for a total ligand was increased by twofold with increasing dose. A mechanism for the increase in the CLeff value might be explained by a saturation of the ANS binding to the intracellular proteins. The hepatocellular distribution and the binding of ANS to cytosolic proteins were then determined. ANS mainly distributed to the cytosol fraction, and the unbound fraction in the cytosol increased from approximately 0.04 to 0.09 when the cytosolic concentrations of ANS increased from 40 to 900 ΜM, respectively. In,spite of such increase in the unbound fraction in the cytosol, the CLseq values remained unchanged with increasing dose, suggesting that the saturation of sequestration clearance for unbound ANS might occur. Furthermore, the plasma disappearance curves of ANS at various doses were simultaneously analyzed based on three nonlinear kinetic models: Model I is a model incorporating both saturable intracellular binding and saturable sequestration; Model II is a model incorporating only saturable intracellular binding; Model III is the model incorporating only saturable sequestration. Goodness- of- fit evaluated by AIC value was best for Model I. Taken together, the nonlinearity in the plasma clearance of ANS was confirmed to be attributed to saturation of both its binding to cytosolic proteins and sequestration process.

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References

  1. B. F. Scharschmidt, J. G. Waggoner, and P. D. Berk. Hepatic organic anion uptake in the rat.J. Clin. Invest. 56:1280–1292 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. C. A. Goresky. Initial distribution and rate of uptake of sulfobromophthalein in the liver.Am. J. Physiol. 207:13–26 (1964).

    CAS  PubMed  Google Scholar 

  3. J.-C. Glasinovic, M. Dumont, M. Duval, and S. Erlinger. Hepatocellular uptake of taurocholate in the dog.J. Clin. Invest. 55:419–426 (1975).

    Article  CAS  Google Scholar 

  4. T. Iga and C. D. Klaassen. Hepatic extraction of nonmetabolizable xenobiotics in rats.J. Pharmacol. Exp. Ther. 211:690–697 (1979).

    CAS  PubMed  Google Scholar 

  5. G. Paumgartner and J. Reichen. Different pathways for hepatic uptake of taurocholate and indocyanine green.Experientia (Basel).32:306–308 (1975).

    Article  Google Scholar 

  6. G. Paumgartner and J. Reichen. Kinetics of hepatic uptake unconjugated bilirubin.Clin. Sci. Mol. Med. 51:169–176 (1976).

    CAS  PubMed  Google Scholar 

  7. J. Reichen and G. Paumgartner. Uptake of bile acids by perfused rat liver.Am. J. Physiol. 231:734–742 (1976).

    CAS  PubMed  Google Scholar 

  8. D. K. F. Meijer, R. J. Vonk, K. Keulemans, and J. G. Weitering. Hepatic uptake and biliary excretion of dibromosulphthalein. Albumin dependence, influence of phenobarbital and nafenopin pretreatment and the role of Y and Z protein.J. Pharmacol. Exp. Ther. 202:8–21 (1977).

    CAS  PubMed  Google Scholar 

  9. U. Gartner, R. J. Stocken, W. G. Levine, and A. W. Wolkoff. Effect of Nafenopin on the uptake of bilirubin and sulfobromophthalein by isolated perfused rat liver.Gastroenterology 83:1163–1169 (1982).

    CAS  PubMed  Google Scholar 

  10. L. Schwarz, R. Burr, M. Schwenk, E. Pfaff, and H. Greim. Uptake of taurocholic acid into isolate rat-liver cells.Eur. J. Biochem. 55:617–623 (1975).

    Article  CAS  PubMed  Google Scholar 

  11. M. Schwenk, R. Burr, L. Schwarz, and E. Pfaff. Uptake of bromosulfophthalein by isolated liver cells.Eur. J. Biochem. 64:189–197 (1976).

    Article  CAS  Google Scholar 

  12. M. S. Anwer, R. Korker, and D. Hegner. Cholic acid uptake into isolated hepatocytes.Hoppe-Seyler's Z. Physiol. Chem. 357:1477–1486 (1976).

    Article  CAS  PubMed  Google Scholar 

  13. S. C. Tsao, Y. Sugiyama, K. Shinmera, Y. Sawada, S. Nagase, T. Iga, and M. Hanano. Protein-mediated hepatic uptake of rose bengal in analbuminemic mutant rats (NAR).Drug Metab. Dispos. 16:482–489 (1988).

    CAS  PubMed  Google Scholar 

  14. Y. Sugiyama, S. Kimura, J. H. Lin, M. Izukura, S. Awazu, and M. Hanano. Effects of organic anions on the uptake of 1-anilino-8-naphthalene sulfonate by isolated liver cells.J. Pharm. Sci. 72:871–876 (1983).

    Article  CAS  PubMed  Google Scholar 

  15. P. D. Berk, B. J. Potter, and W. Stremmel. Role of plasma membrane ligand-binding proteins in the hepatocellular uptake of albumin-bound organic anions.Hepatology 7:165–176 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. R. Weisiger, J. Gollan, and R. K. Ockner. Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin-bound substances.Science 211:1048–1051 (1981).

    Article  CAS  PubMed  Google Scholar 

  17. R. K. Ockner, R. A. Weiseger, and J. L. Gollan. Hepatic uptake of albumin-bound substances: The albumin receptor concept.Am. J. Physiol. 245:613–618 (1983).

    Google Scholar 

  18. E. L. Forker and B. A. Luxon. Albumin helps mediate removal of taurocholate by rat liver.J. Clin. Invest. 67:1517–1522 (1981).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. E. L. Forker and B. A. Luxon. Hepatic transport and binding of rose bengal in the presence of albumin and gamma globulin.Am. J. Physiol. 248:G702-G708 (1985).

    CAS  PubMed  Google Scholar 

  20. E. L. Forker and B. A. Luxon. Effects of unstirred disse fluid, nonequilibrium binding, and surface-mediated dissociation on hepatic removal of albumin-bound organic anions.Am. J. Physiol. 248:G709-G717 (1985).

    CAS  PubMed  Google Scholar 

  21. R. A. Weisiger. Dissociation from albumin: A potentially rate-limiting step in the clearance substances by the liver.Proc. Natl. Acad. Sci. 82:1563–1567 (1985).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. P. V. D. Sluijs, B. Postema, and K. F. Meijer. Lactosylation of albumin reduces uptake rate of dibromosulfophthalein in perfused rat liver and dissociation rate from albumin in vitro.Hepatology 7:688–695 (1987).

    Article  PubMed  Google Scholar 

  23. A. J. Levi, Z. Gatmaitan, and I. M. Arias. Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions.J. Clin. Invest. 48:2156–2167 (1969).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. G. Litwack, B. Ketterer, and I. M. Arias. Ligandin: a hepatic protein which binds steroids, bilirubin, carcinogens and a number of exogenous organic anions.Nature 234:466–467 (1971).

    Article  CAS  PubMed  Google Scholar 

  25. W. H. Habig, M. J. Pabst, G. Fleischner. Z. Gatmaitan, I. M. Arias, and W. B. Jakoby. The identity of glutathion S-transferase B with ligandin, a major binding protein of liver.Proc. Natl. Acad. Sci. 71:3879–3882 (1974).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. A. W. Wolkoff, C. A. Goresky, J. Sellin, Z. Gatmaitan, and I. M. Arias. Role of ligandin in transfer of bilirubin from plasma into liver.Am. J. Physiol. 236:638–648 (1979).

    Google Scholar 

  27. Y. Sugiyama, T. Yamada, and N. Kaplowitz. Glutathion S-transferases in elasmobranch liver.Biochem. J. 199:749–756 (1981).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Y. Sugiyama, T. Yamada, and N. Kaplowitz. Newly identified organic anion-binding proteins in rat liver cytosol.Biochim. Biophys. Acta 709:342–352 (1982).

    Article  CAS  PubMed  Google Scholar 

  29. Y. Sugiyama, T. Yamada, and N. Kaplowitz. Newly identified bile acid binders in rat liver cytosol.J. Biol. Chem. 258:3602–3607 (1983).

    CAS  PubMed  Google Scholar 

  30. L. Stryer. Fluorescence spectroscopy of proteins. Fluorescent probes provide insight into the structure, interactions, and dynamics of proteins.Science 162:526–533 (1968).

    Article  CAS  PubMed  Google Scholar 

  31. B. Rabalcava, D. Martinez de Munoz, and C. Gitler, Interaction of fluorescent probes with membranes. I. Effect of ions on erythrocyte membranes.Biochemistry 8:2742–2747 (1969).

    Article  Google Scholar 

  32. P. A. G. Fortes and J. F. Hoffman. Interactions of the fluorescent anion ANS with membrane charge in human red cell ghosts.J. Membrane Biol. 5:154–168 (1971).

    Article  CAS  Google Scholar 

  33. S. Cheng and D. Levy. The interaction of the anionic fluorescence probe, ANS, with hepatocytes and hepatoma tissue culture cells.Biochem. Biophys. Acta 511:419–429 (1978).

    Article  CAS  PubMed  Google Scholar 

  34. T. Nakagawa, Y. Koyanagi, and H. Togawa.SALS, a Computer Program for Statistical Analysis with Least Squares Fitting. Library program of the University of Tokyo Computer Center, Tokyo, Japan, 1978.

    Google Scholar 

  35. J. H. Lin, Y. Sugiyama, S. Awazu, and M. Hanano. In vitro and in vivo evaluation of tissue-to-plasma partition coefficient for physiological pharmacokinetic model.J. Pharmacokin. Biopharm. 10:637–647 (1982).

    Article  CAS  Google Scholar 

  36. W. B. Jakoby, W. H. Habig, J. H. Keen, J. N. Ketley, and M. J. Pabst.Glutathione: Metabolism and Function, Raven Press, New York, 1976, pp. 189–200.

    Google Scholar 

  37. T. Iga, M. Yokota, Y. Sugiyama, S. Awazu, and M. Hanano. Hepatic transport of indocyanine green in rats chronically intoxicated with carbon tetrachloride.Biochem. Pharmacol. 29:1291–1297 (1980).

    Article  CAS  PubMed  Google Scholar 

  38. K. Yamaoka, T. Nakagawa, and T. Uno. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations.J. Pharmacokin. Biopharm. 6:165–175 (1978).

    Article  CAS  Google Scholar 

  39. D. K. F. Meijer, A. Blom, J. G. Weitering, and R. Hornsveld. Pharmacokinetics of the hepatic transport of organic anions: Influence of extra- and intracellular binding on hepatic storage of dibromosulfophthalein and interactions with indocyanine green.J. Pharmacokin. Biopharm. 12:43–65 (1984).

    Article  CAS  Google Scholar 

  40. S. Miyauchi, Y. Sugiyama, Y. Sawada, K. Morita, T. Iga, and M. Hanano. Kinetics of hepatic transport of 4-methylumbelliferone in rats. Analysis by multiple inducator dilution method.J. Pharmacokin. Biopharm. 15:25–38 (1987).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan

    Youn Bok Chung, Seiji Miyauchi, Yuichi Sugiyama, Hideyoshi Harashima, Tatsuji Iga & Manabu Hanano

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  1. Youn Bok Chung
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  2. Seiji Miyauchi
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Chung, Y.B., Miyauchi, S., Sugiyama, Y. et al. Kinetic analysis of the dose-dependent hepatic handling of 1-anilino-8-naphthalene sulfonate in rats. Journal of Pharmacokinetics and Biopharmaceutics 18, 313–333 (1990). https://doi.org/10.1007/BF01062271

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