Skip to main content
SpringerLink
Log in

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

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  6. W. Colburn. Albumin does not mediate the removal of taurocholate by rat liver.J. Pharm. Sci. 71:373–374 (1982).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  10. S. Keiding and E. Steiness. Flow dependence of propranolol elimination in perfused rat liver.J. Pharmacol. Exp. Ther. 230:474–477 (1984).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  13. L. Bass. Saturation kinetics in hepatic drug removal: A statistical approach to functional heterogeneity.Am. J. Physiol. 244:G583-G589 (1983).

    CAS  PubMed  Google Scholar 

  14. M. S. Roberts and M. Rowland. Hepatic elimination-dispersion model.J. Pharm. Sci. 74:585–587 (1985).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. L. Bass and S. Keiding. Physiologically based models and strategic experiments in hepatic pharmacology.Biochem. Pharmacol. 37:1425–1431 (1988).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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. C. V. Greenway and G. Oshiro. Effects of histamine on hepatic volume (outflow block) in anaesthetised dogs.Br. J. Pharmacol. 47:282–290 (1973).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Michael S. Roberts

    Present address: Departments of Pharmacy and Medicine, University of Queensland, 4067, St. Lucia, Queensland, Australia

Authors and Affiliations

  1. Department of Pharmacy, Otago Medical School, Dunedin, New Zealand

    Michael S. Roberts

  2. School of Pharmacy, University of Tasmania, Hobart, Australia

    Sharon Fraser & Andrew Wagner

  3. Department of Physiology, University of Tasmania, Hobart, Australia

    Lyndsay McLeod

Authors
  1. Michael S. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon Fraser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lyndsay McLeod
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This study was supported by the National Health and Medical Research Council of Australia and the Dean's MRC (NZ) Fund.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roberts, M.S., Fraser, S., Wagner, A. et al. 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. Journal of Pharmacokinetics and Biopharmaceutics 18, 235–258 (1990). https://doi.org/10.1007/BF01062201

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01062201

Key words

Search

Navigation