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Residence time distributions of solutes in the perfused rat liver using a dispersion model of hepatic elimination: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate

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Abstract

The residence time distributions of sucrose and taurocholate have been determined from the outflow concentration-time profiles after bolus input into an in situperfused rat liver preparation. The normalized variance (and the dispersion number) appeared to be independent of perfusate flow rate (10 to 37ml/mm) and perfusate albumin concentration (0–5%). The apparent volume of distribution for sucrose appeared to increase with flow rate but was unaffected by the concentration of albumin (0–5%) present in the perfusate. The changes in taurocholate availability with flow rate were adequately accounted for by the dispersion model, whereas taurocholate availabilityprotein binding changes required an albumin-mediated transport model to be used in conjunction with the dispersion model.

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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 liverin 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. Gibaldi and G. Perrier.Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982, pp. 409–417.

    Google Scholar 

  21. A. W. Woikoff, C. A. Goresky, J. Selkin, Z. Gatmaiten, and I. M. Arias. Role of ligandin in the transfer of bilirubin from plasma into liver.Am. J. Physiol. 236:E638-E648 (1979).

    Google Scholar 

  22. C. A. Goresky, A linear method for determining liver sinusoidal and extravascular volume.Am. J. Physiol. 204:626–640 (1963).

    CAS  PubMed  Google Scholar 

  23. C. A. Goresky. Kinetic interpretation of hepatic multiple-indicator studies.Am. J. Physiol. 245:G1-G12 (1983).

    CAS  PubMed  Google Scholar 

  24. 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 

  25. J. M. Pries, A. B. Staples, and R. F. Hanson. The effect of hepatic blood flow on taurocholate extraction by the isolated perfused rat liver.J. Lab. Clin. Med. 97:412–417 (1981).

    CAS  PubMed  Google Scholar 

  26. L. Bass, M. S. Roberts, and P. J. Robinson. On the relation between extended forms of the sinusoidal perfusion and of the convection-dispersion models of hepatic elimination.J. Theoret. Biol. 126:457–482 (1987).

    Article  CAS  Google Scholar 

  27. R. H. Smallwood, D. J. Morgan, G. W. Mihaly, and R. A. Smallwood. Lack of linear correlation between hepatic ligand uptake rate and unbound ligand concentration does not necessarily imply receptor mediated uptake.J. Pharmacokin. Biopharm. 16:397–411 (1988).

    Article  CAS  Google Scholar 

  28. R. H. Smallwood, D. J. Morgan, D. B. Jones, G. W. Mihaly, and R. A. Smailwood. Effect of plama protein binding on elimination of taurocholate by isolated perfused rat liver—comparison of venous equilibrium undistributed and distributed sinusoidal and dispersion models.J. Pharmacokin. Biopharm. 16:377–396 (1988).

    Article  CAS  Google Scholar 

  29. R. Weisiger, J. Gollen, and R. 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 

  30. 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 

  31. L. Schwarz, R. Burr, M. Schwark, E. Pfaff, and H. Greim. Uptake of taurocholate acid into isolated rat liver cells.Em. J. Biochem. 55:617–623 (1975).

    Article  CAS  Google Scholar 

  32. T. Iga and C. D. Klaassen. Uptake of bile acids by isolated rat hepatocytes.Biochem. Pharmacol. 31:211–216 (1982).

    Article  CAS  PubMed  Google Scholar 

  33. P. V. Dippe and D. Levy. Characterisation of the bile acid transport system in normal transformed hepatocytes: photoaffinity labelling of the taurocholate carrier protein.J. Biol. Chem. 258:8896–8901 (1983).

    Google Scholar 

  34. 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 

  35. N. E. Huffman, J. H. Iser, and R. A. Smallwood. Hepatic bile transport: effect of conjugation and position of hydroxyl groups.Am. J. Physiol. 229:298–302 (1975).

    Google Scholar 

  36. R. A. Weisiger, C. M. Zacks, N. D. Smith, and J. L. Boyer. Effect of albumin binding on extraction of sulfobromophthalin by perfused elasmobranch liver: evidence for dissociation limited uptake.Hepatology 4:492–501 (1984).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

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

    Article  PubMed  Google Scholar 

  39. A. W. Wolkoff. The role of an albumin receptor in hepatic organic anion uptake: the controversy continues.Hepatology 7:777–779 (1987).

    Article  CAS  PubMed  Google Scholar 

  40. P. D. I. Richardson and P. G. Withrington. Liver blood flow. I. Intrinsic and nervous control of liver blood flow.Gastroenterology 81:159–173 (1981).

    CAS  PubMed  Google Scholar 

  41. P. D. I. Richardson and P. G. Withrington. Liver blood flow. II. Effects of drugs and hormones on liver blood flow.Gastroenterology 81:356–375 (1981).

    CAS  PubMed  Google Scholar 

  42. 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 

  43. A. M. Thompson, H. M. Cavert, and N. Lifson. Kinetics of distribution of D2O and antipyrine in isolated perfused rat liver.Am. J. Physiol. 192:531–537 (1958).

    CAS  PubMed  Google Scholar 

  44. A. M. Thompson, H. M. Cavert, N. Lifson, and R. L. Evans. Regional tissue uptake of D2O in perfused organs: rat liver, dog heart and gastocnemius.Am. J. Physiol. 197:897–902 (1959).

    CAS  Google Scholar 

  45. W. O. Griffen, D. G. Levitt, C. J. Ellis, and N. Lifson. Intrahepatic distribution of hepatic blood flow: single-input studies.Am. J. Physiol. 218:1474–1479 (1970).

    PubMed  Google Scholar 

  46. N. Lifson, D. G. Levitt, W. O. Griffen, and C. J. Ellis. Intrahepatic distribution of hepatic blood flow: double-input studies.Am. J. Physiol. 218:1480–1488 (1970).

    CAS  PubMed  Google Scholar 

  47. M. S. Roberts, J. D. Donaldson, and D. R. Jackett. Availability predictions by hepatic elimination models for Michaelis-Menten kinetics.J. Pharmacokin. Biopharmaceut. 17:687–719 (1989).

    Article  CAS  Google Scholar 

  48. B. C. Sherrill and J. M. Dietschy. Characterisation of the sinusoidal transport process responsible for uptake of chylomicrons by the liver.J. Biol. Chem. 253:1859–1867 (1978).

    CAS  PubMed  Google Scholar 

  49. D. B. Jones, G. W. Mihaly, R. A. Smallwood, L. K. Webster, D. J. Morgan, and N. P. Madsen. Differential effects of hypoxia on the disposition of propranol and sodium taurocholate by the isolated perfused rat liver.Hepatology 4:461–466 (1984).

    Article  CAS  PubMed  Google Scholar 

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

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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: 1. Effect of changes in perfusate flow and albumin concentration on sucrose and taurocholate. Journal of Pharmacokinetics and Biopharmaceutics 18, 209–234 (1990). https://doi.org/10.1007/BF01062200

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