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Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 2. Effect of pharmacological agents, retrograde perfusions, and enzyme inhibition on evans blue, sucrose, water, and taurocholate

  • Michael S. Roberts
  • Sharon Fraser
  • Andrew Wagner
  • Lyndsay McLeod
Article

Abstract

The effect of altered physiological conditions on the residence time distributions of sucrose, water, and taurocholate in the rat liver were studied using a bolus injection and quantifying fraction of total outflow per ml-time profiles. Retrograde perfusions increased the residence times of sucrose and water markedly and were associated with very low hepatic availabilities for taurocholate. Resistance by the inlet sinusoids sphincters, which become outlet sphincters during retrograde perfusions, is suggested as the explanation for the observation. Infusions of noradrenaline, propranolol, and lidocaine resulted in relatively small changes in the mean residence times for sucrose and water with no apparent relationship existing between the efficiency number of taurocholate and volumes of either water or sucrose. Taurochenodeoxycholate resulted in an increase in the availability and mean residence time for taurocholate relative to no infusion.

Key words

liver metabolism hepatic models residence time distribution dispersion model drug infusions enzyme inhibition retrograde perfusion rat liver 

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References

  1. 1.
    K. S. Pang and M. Rowland. Hepatic clearance of drugs: I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding and hepatocellular enzymatic activity on hepatic drug clearance.J. Pharmacokin. Biopharm. 5:625–653 (1977).CrossRefGoogle Scholar
  2. 2.
    K. S. Pang and M. Rowland. Hepatic clearance of drugs: II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused ratin situ preparation.J. Pharmacokin. Biopharm. 5:655–680 (1977).CrossRefGoogle Scholar
  3. 3.
    K. S. Pang and M. Rowland. Hepatic clearance of drugs: III. Additional experimental evidence supporting the “well-stirred” model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused liver in situ preparation.J. Pharmacokin. Biopharm. 5:681–699 (1977).CrossRefGoogle Scholar
  4. 4.
    A. B. Ahmad, P. N. Bennett, and M. Rowland. Models of hepatic drug clearance: Discrimination between the ‘well-stirred’ and ‘parallel tube’ models.J. Pharm. Pharmacol. 35:219–224 (1983).PubMedCrossRefGoogle Scholar
  5. 5.
    D. B. Jones, D. J. Morgan, G. W. Mihaly, L. K. Webster, and R. A. Smallwood. Discrimination between the venous equilibrium and sinusoidal models of hepatic drug elimination in the isolated perfused rat liver by perturbation of propranolol protein binding.J. Pharmacol. Exp. Ther. 229:522–526 (1984).PubMedGoogle Scholar
  6. 6.
    W. Colburn. Albumin does not mediate the removal of taurocholate by rat liver.J. Pharm. Sci. 71:373–374 (1982).PubMedCrossRefGoogle Scholar
  7. 7.
    K. S. Pang and J. R. Gillette. Kinetics of metabolite formation and elimination in the perfused rat liver preparation: Differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin.J. Pharmacol. Exp. Ther. 207:178–194 (1978).PubMedGoogle Scholar
  8. 8.
    S. Keiding and E. Chiarantini. Effect of sinusoidal perfusion on galactose elimination in perfused rat liver.J. Pharmacol. Exp. Ther. 205:465–470 (1978).PubMedGoogle Scholar
  9. 9.
    M. Rowland, K. Leitch, G. Fleming, and B. Smith. Protein binding and hepatic clearance: Discrimination between models of hepatic clearance with diazepam, a drug of high intrinsic clearance, in the isolated perfused rat liver preparation.J. Pharmacokin. Biopharm. 12:129–147 (1984).CrossRefGoogle Scholar
  10. 10.
    S. Keiding and E. Steiness. Flow dependence of propranolol elimination in perfused rat liver.J. Pharmacol. Exp. Ther. 230:474–477 (1984).PubMedGoogle Scholar
  11. 11.
    L. Bass, P. J. Robinson, and A. J. Bracken. Hepatic elimination of flowing substances: The distributed model.J. Theoret. Biol. 72:161–184 (1978).CrossRefGoogle Scholar
  12. 12.
    E. L. Forker and B. Luxon. Hepatic transport kinetics and plasma disappearance curves. Distributed modelling versus conventional approach.Am. J. Physiol. 235:E648-E660 (1978).PubMedGoogle Scholar
  13. 13.
    L. Bass. Saturation kinetics in hepatic drug removal: A statistical approach to functional heterogeneity.Am. J. Physiol. 244:G583-G589 (1983).PubMedGoogle Scholar
  14. 14.
    M. S. Roberts and M. Rowland. Hepatic elimination-dispersion model.J. Pharm. Sci. 74:585–587 (1985).PubMedCrossRefGoogle Scholar
  15. 15.
    M. S. Roberts and M. Rowland. A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations.J. Pharmacokin. Biopharm. 14:227–260 (1986).CrossRefGoogle Scholar
  16. 16.
    M. S. Roberts and M. Rowland. A dispersion model of hepatic elimination: 2. Steady-state considerations. Influence of blood flow, protein binding and hepatocellular enzymatic activity.J. Pharmacokin. Biopharm. 14:261–288 (1986).CrossRefGoogle Scholar
  17. 17.
    M. S. Roberts and M. Rowland. A dispersion model of hepatic elimination: 3. Application to metabolite formation and elimination kinetics.J. Pharmacokin. Biopharm. 14:289–308 (1986).CrossRefGoogle Scholar
  18. 18.
    M. S. Roberts and M. Rowland. Correlation between in vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model.J. Pharm. Pharmacol. 38:117–181 (1986).CrossRefGoogle Scholar
  19. 19.
    M. S. Roberts, J. D. Donaldson, and M. Rowland. Models of hepatic elimination: Comparison of stochastic models to describe residence time distributions and to predict the influence of drug distribution, enzyme heterogeneity and systemic recycling or hepatic elimination.J. Pharmacokin. Biopharm. 16:41–84 (1988).CrossRefGoogle Scholar
  20. 20.
    M. S. Roberts, S. Fraser, A. Wagner, and L. J. McLeod. Residence time distributions of solutes in the perfused rat liver using the dispersion model of hepatic elimination: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate.J. Pharmacokin. Biopharm. 18: 209–234 (1990).CrossRefGoogle Scholar
  21. 21.
    E. L. Forker and B. A. Luxon. Albumin helps moderate removal of taurocholate by rat liver.J. Clin. Invest. 67:1517–1522 (1981).PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    L. Bass and S. Keiding. Physiologically based models and strategic experiments in hepatic pharmacology.Biochem. Pharmacol. 37:1425–1431 (1988).PubMedCrossRefGoogle Scholar
  23. 23.
    R. A. Weisiger. Dissociation from albumin: A potentially rate-limiting step in the clearance of substances by the liver.Proc. Natl. Acad. Sci. U.S.A 82: 1563–1567 (1985).PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    K. S. Pang and J. A. Terrell. Retrograde perfusion to probe the heterogeneous distribution of hepatic drug metabolising enzymes in rats.J. Pharmacol. Exp. Ther. 216:339–346 (1981).PubMedGoogle Scholar
  25. 25.
    K. S. Pang, H. Koster, I. C. M. Halsema, E. Scholters, G. J. Milder, and R. N. Stillwell. Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation.J. Pharmacol Exp. Ther. 224:647–653 (1983).PubMedGoogle Scholar
  26. 26.
    K. S. Pang, J. A. Terrell, S. D. Nelson, K. F. Feuer, J.-J. Clements, and L. Endrenyi. An enzyme distributed system for lidocaine metabolism in the perfused rat liver preparation.J. Pharm. Biopharm. 14:107–130 (1986).CrossRefGoogle Scholar
  27. 27.
    M. V. St-Pierre, A. J. Schwab, C. A. Goresky, W. Lee, and K. S. Pang. The multiple-indicator dilution technique for characterisation of normal and retrograde flow in once-through rat liver perfusions.Hepatology 9:285–296 (1989).PubMedCrossRefGoogle Scholar
  28. 28.
    P. D. I. Richardson and P. G. Withrington. Liver blood flow. 1. Intrinsic and nervous control of liver blood flow.Gastroenterology 81:159–173 (1981).PubMedGoogle Scholar
  29. 29.
    P. D. I. Richardson and P. G. Withrington. Liver blood flow. 2. Effects of drugs and hormones on liver blood flow.Gastroenterology 81:356–375 (1981).PubMedGoogle Scholar
  30. 30.
    J. L. Campra and T. B. Reynolds. The hepatic circulation. In I. Arias, D. Popper, D. Schatchter, and D. A. Shafritz (eds.),The Liver Biology and Pathobiology, Raven, NY, chap. 37, pp. 627–645 (1982).Google Scholar
  31. 31.
    C. V. Greenway and G. Oshiro. Effects of histamine on hepatic volume (outflow block) in anaesthetised dogs.Br. J. Pharmacol. 47:282–290 (1973).PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    G. M. M. Groothuis, M. J. Hardonk, K. P. T. Keulemans, P. Nieuwenhuis, and D. K. M. Meijer. Autoradiographic and kinetic demonstration of acinar heterogeneity of taurocholate transport.Am. J. Physiol. 243:G455-G462 (1982).PubMedGoogle Scholar
  33. 33.
    L. R. Schwarz, R. Burr, M. Schwerk, E. Pfaff, and H. Greim. Uptake of taurocholic acid into isolated rat-liver cells.Eur. J. Biochem. 55: 617–623 (1975).PubMedCrossRefGoogle Scholar
  34. 34.
    G. J. Gores, L. J. Kost, and N. F. LaRusso. The isolated perfused rat liver: Conceptual and practical considerations.Hepatology 6: 511–517 (1986).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Michael S. Roberts
    • 1
  • Sharon Fraser
    • 2
  • Andrew Wagner
    • 2
  • Lyndsay McLeod
    • 3
  1. 1.Department of PharmacyOtago Medical SchoolDunedinNew Zealand
  2. 2.School of PharmacyUniversity of TasmaniaHobartAustralia
  3. 3.Department of PhysiologyUniversity of TasmaniaHobartAustralia

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