Advertisement

Physiologic Models of Hepatic Drug Elimination

  • Malcolm Rowland
  • Allan M. Evans
Part of the NATO ASI Series book series (NSSA, volume 221)

Abstract

Pharmacokinetic models are used primarily to describe the time course of drugs and metabolites in the body following various routes of administration. Such models take a variety of forms. Some are simply descriptive, comprising mathematical equations which make no reference to underlying physiology. The ability to use such descriptive models to interpret pharmacokinetic data and to predict outcome under a variety of conditions is extremely limited. Pharmacokinetic models which are physiologically based have greater application and have enjoyed wide usage, particularly those applied to the elimination of drugs by the liver and, to a lesser extent, by the kidneys [Rowland & Tozer, 1989]. The present chapter reviews the physiologic models that have been applied to hepatic clearance, focusing on recent advances, and comments on some problems and outstanding issues. Mention is also made of the usefulness of the isolated perfused liver for investigating drug distribution and elimination kinetics.

Keywords

Human Serum Albumin Dispersion Model Hepatic Clearance Intrinsic Clearance Residence Time Distribution 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahmad, A.B., Bennett, P.N., Rowland, M., 1983. Models of hepatic drug clearance: discrimination between the “well-stirred” and “parallel-tube” models. J. Pharm. Pharmacol. 35: 219.PubMedCrossRefGoogle Scholar
  2. Barnhart, J.L., Witt, B.L., Hardison, W.G., Berk, R.N., 1983. Uptake of iopanoic acid by isolated rat hepatocytes in primary culture, Am. J. Physiol. 244: 630.Google Scholar
  3. Bass, L., Pond, S.M., 1988. The puzzle of rates of cellular uptake of protein bound ligands. In: “Pharmacokinetics: Mathematical and Statistical Approaches to Metabolism and Distribution of Chemicals and Drugs” ( A. Pecile and A. Rescigno, eds), page 245. Plenum Press, New York.Google Scholar
  4. Bass, L., Roberts, M.S., Robinson, P.J., 1987. On the relation between extended forms of the sinusoidal perfusion and of the convection-dispersion models of hepatic elimination. J. Theor. Biol. 126: 457.PubMedCrossRefGoogle Scholar
  5. Bass, L., Robinson, P., Bracken, A.J., 1978. Hepatic elimination of flowing substrates: The distributed model. Theor. Biol. 72: 161.CrossRefGoogle Scholar
  6. Burczynski, F.J., Cai, Z.-S., Moran, J.B., Forker, E.L., 1989. Palmitate uptake by cultured hepatocytes: albumin binding and stagnant layer phenomenon. Am. J. Physiol. 257: G584.PubMedGoogle Scholar
  7. Ching, M.S., Morgan, D.J., Smallwood, R.A., 1989. Models of hepatic elimination: implications from studies of the simultaneous elimination of tauracholate and diazepam by isolated rat liver under varying conditions of binding. J. Pharmacol. Exp. Ther. 250: 1048.PubMedGoogle Scholar
  8. Colburn, W.A., 1982. Albumin does not mediate the removal of tauracholate by the rat liver. J. Pharm. Sci. 71: 373.PubMedCrossRefGoogle Scholar
  9. Colburn, W.A., 1983. Albumin binding and hepatic uptake: the importance of model selection - a response. J. Pharm. Sci. 72: 1233.CrossRefGoogle Scholar
  10. de Lannoy, I.A.M., Pang, K.S., 1987. Diffusional barriers on drug and metabolite kinetics. Drug Metab. Dispos. 15: 51.Google Scholar
  11. Evans, A.M., Hussein, Z., Rowland, M., 1991. A two-compartment dispersion model describes the hepatic outflow profile of diclofenac in the presence of its binding protein. J. Pharm. Pharmacol.Google Scholar
  12. Fleischer, A.B., Shurmantine, W.O., Luxon, B.A., Forker, E.L., 1986 Palmitate uptake by hepatocyte monolayers. Effect of albumin binding. J. Clin. Invest. 77: 964.PubMedCrossRefGoogle Scholar
  13. Forker, E.L., Luxon, B., 1978. Hepatic transport kinetics and plasma disappearance curves: distributed modeling versus conventional approach. Am. J. Physiol. 235: E648PubMedGoogle Scholar
  14. Forker, E.L., Luxon, B.A., 1981. Albumin helps mediate removal of tauracholate by rat liver. J. Clin. Invest. 67: 1517.PubMedCrossRefGoogle Scholar
  15. Forker E.L., Luxon, B.A., 1983a. Albumin binding and hepatic uptake: the importance of model selection. J. Pharm. Sci. 72: 1232.PubMedCrossRefGoogle Scholar
  16. Forker, E.L., Luxon, B.A., 1983b. Analyzing tracer disappearance curves to study hepatic transport kinetics. Am. J. Physiol. 244: G573.PubMedGoogle Scholar
  17. Forker, E.L., Luxon, B.A., 1985a. Effects of unstirred Disse fluid, nonequilibrium binding, and surface-mediated dissociation on hepatic removal of albumin-bound organic anions. Am. J. Physiol. 248: G709.PubMedGoogle Scholar
  18. Forker, E.L., Luxon, B.A., 1985b. Lumpers vs. distributers. Hepatology 5: 1236.PubMedCrossRefGoogle Scholar
  19. Forker, E.L., Luxon, B.A., 1986. Models of hepatic elimination: a critical commentary. Hepatology 6: 340.PubMedCrossRefGoogle Scholar
  20. Forker, E.L., Luxon, B.A., Snell, M., Shurmantine, W.O., 1982. Effect of albumin binding on the hepatic transport of rose bengal: surface mediated dissociation of limited capacity. J. Pharmacol. Exp. Ther. 233: 342.Google Scholar
  21. Goresky, C.A., 1983. Kinetic interpretation of hepatic multiple-indicator dilution studies. Am. J. Physiol. 245: G1.PubMedGoogle Scholar
  22. Goresky, C.A., Bach, G.G., Nadeau, B.E., 1975. Red cell carriage of label: its limiting effect on the exchange of materials in the liver. Circ. Res. 36: 328.PubMedGoogle Scholar
  23. Goresky, C.A., Rose, C.P., 1977. Blood-tissue exchange in liver and heart: the influence of heterogeneity of capillary transit times. Fed. Proc. 36: 2629.PubMedGoogle Scholar
  24. Goresky, C.A., Silverman, M., 1964. Effect of correction of catheter distortion on calculated liver sinusoidal volumes. Am. J. Physiol. 207: 883.PubMedGoogle Scholar
  25. Gumucio, J.J., 1983. Functional and anatomic heterogeneity in the liver acinus: impact on transport. Am. J. Physiol. 244: G578.PubMedGoogle Scholar
  26. Horie, T., Mizuma, T., Kasai, S., Awazu, S., 1988. Conformational change in plasma albumin due to interaction with isolated rat hepatocyte. Am. J. Physiol. 254: G465.PubMedGoogle Scholar
  27. Jansen, J.A., 1981. Influence of plasma protein binding kinetics on hepatic clearance assessed from a “tube” model and a “well-stirred” model. J. Pharmacokin. Biopharm. 9: 15.CrossRefGoogle Scholar
  28. Jones, D.B., Morgan, D.J., Mihaly, G.W., Webster, L.K., Smallwood, R.A., 1984. 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.PubMedGoogle Scholar
  29. Jones, D.R., Hall, S.D., Jackson, E.K., Branch, R.A., Wilkinson, G.R., 1988. Brain uptake of benzodiazepines: effect of lipophilicity and plasma protein binding. J. Pharmacol. Exp. Ther. 245: 816.PubMedGoogle Scholar
  30. Keiding, S., Chiarantini, E., 1978. Effect of sinusoidal perfusion on galactose elimination kinetics in perfused rat liver. J. Pharmacol. Exp. Ther. 204: 465.Google Scholar
  31. Lee, H.-J., Chiou, W.L., 1989a. Erythrocytes as barriers for drug elimination in the isolated rat liver. I. Doxorubicin. Pharm. Res. 6: 833.CrossRefGoogle Scholar
  32. Lee, H.-J., Chiou, W.L., 1989b. Erythrocytes as barriers for drug elimination in the isolated rat liver. II. Propranolol. Pharm. Res. 6: 840.CrossRefGoogle Scholar
  33. Levenspiel, O., 1972. “Chemical Reaction Engineering”, pages 253–315. Wiley, New York.Google Scholar
  34. Luxon, B.A., Forker, E.L., 1982. Simulation and analysis of hepatic indicator dilution curves. Am. J. Physiol. 243: G76.PubMedGoogle Scholar
  35. Luxon, B.A., King, P.D., Forker, E.L., 1982. How to measure first-order hepatic transfer coefficients by distributed modeling of a recirculating rat liver perfusion system. Am. J. Physiol. 243: G518.PubMedGoogle Scholar
  36. Miyauchi, S., Sugiyama, Y., Sawada, Y., Morita, K., Iga, T., Hanano, M., 1987. Kinetics of hepatic transport of 4-methylumbelliferone in rats. Analysis by multiple indicator dilution method. J. Pharmacokin. Biopharm. 15: 25.CrossRefGoogle Scholar
  37. Mizuma, T., Horie, T., Awazu, S., 1985. The effect of albumin on the uptake of bromosulfophthalein by isolated rat hepatocytes,. J. Pharmacobio-Dyn. 8: 90.PubMedCrossRefGoogle Scholar
  38. Morgan, D.J., Jones, D.B., Smallwood, R.A., 1985. Modeling of substrate elimination by the liver: has the albumin receptor model superseded the well-stirred model ? Hepatology 5: 1231.PubMedCrossRefGoogle Scholar
  39. Morgan, D.J., Raymond, K., 1982. Use of unbound drug concentration in blood to discriminate between two models of hepatic drug elimination. J. Pharm. Sci. 71: 600.PubMedCrossRefGoogle Scholar
  40. Morgan, D.J., Smallwood, R.A., 1990. Clinical significance of pharmacokinetic models of hepatic elimination. Clin. Pharmacokin. 18: 61.CrossRefGoogle Scholar
  41. Nunes, R., Kiang, C.-L., Sorrentino, D., Berk, P.D., 1988. “Albumin-receptor” uptake kinetics do not require an intact lobular architecture and are not specific for albumin. J. Hepatology 7:293.CrossRefGoogle Scholar
  42. Oie, S., Fiori, F., 1985. Effect of albumin and alpha-1-acid glycoprotein on elimination of prazocin and antipyrine in the isolated perfused rat liver. J. Pharmacol. Exp. Ther. 234: 636.PubMedGoogle Scholar
  43. Pang, K.S., 1983. The effects of intercellular distribution of drug metabolizing enzymes on the kinetics of stable metabolite formation and elimination by liver: first-pass effects. Drug Metab. Rev. 14: 61.Google Scholar
  44. Pang, K.S., Mulder, G.J., 1990. The effect of hepatic blood flow on formation of metabolites. Drug Metab. Dispos. 18: 270.Google Scholar
  45. Pang, K.S., Rowland, M., 1977a. Hepatic clearance of drugs. 1. 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.CrossRefGoogle Scholar
  46. Pang, K.S., Rowland, M., 1977b. Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel-tube” model using lidocaine in the perfused rat liver in situ preparation. J. Pharmacokin. Biopharm. 5: 655.CrossRefGoogle Scholar
  47. Pang, K.S., Stillwell, R.N., 1983. An understanding of the role of enzymic localization of the liver on metabolite kinetics: a computer simulation. J. Pharmacokin. Biopharm. 11: 451.CrossRefGoogle Scholar
  48. Pardridge, W.M., 1986. Transport of plasma protein-bound drugs into tissues in vivo. In: “Symposia Medica Hoechst, Volume 20: Protein binding and drug transport” ( J.-P. Tillement and E. Lindenlaub, eds.). Schattauer Verlag, New York.Google Scholar
  49. Roberts, M.S, Donaldson, J.D., Jackett, D., 1989. Availability predictions by hepatic elimination models for Michaelis-Menten kinetics. J. Pharmacokin. Biopharm. 17: 687.CrossRefGoogle Scholar
  50. Roberts, M.S., Donaldson, J.D., Rowland, M., 1988. 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 on hepatic elimination. J. Pharrnacokin. Biopharm. 16: 41.CrossRefGoogle Scholar
  51. Roberts, M.S., Fraser, S., Wagner, A., McLeod, L., 1990. 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 tauracholate. J. Pharmacoldn. Biophartn. 18: 209.CrossRefGoogle Scholar
  52. Roberts, M.S., Rowland, M., 1986a. Correlation between in-vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model. J. Pharm. Pharmacol. 38: 177.PubMedCrossRefGoogle Scholar
  53. Roberts, M.S., Rowland, M., 1986b. A dispersion model of hepatic elimination. 1. Formulation of the model and bolus considerations. J. Pharrnacokin. Biopharm. 14: 227.CrossRefGoogle Scholar
  54. Roberts, M.S., Rowland, M., 1986c. A dispersion model of hepatic elitnination. 2. Steady-state considerations - influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity. J. Pharmacoldn. Biopharrn. 14: 261.CrossRefGoogle Scholar
  55. Rowland, M., Leitch, D., Fleming, G., Smith, B., 1984. 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.CrossRefGoogle Scholar
  56. Rowland, M., Tozer, T.N., 1989. “Clinical Pharmacokinetics: concepts and applications”, Second edition. Lea & Febiger, Philadelphia.Google Scholar
  57. Schwab, A.J., Barker, F., Goresky, C.A., Pang, K.S., 1990. Transfer of enalaprilat across rat liver cell membranes is barrier limited. Am. J. Physiol. 258: G461.PubMedGoogle Scholar
  58. Smallwood, R.H., Morgan, D.J., Mihaly, G.W., Jones, D.B., Smallwood, R.A., 1988. Effect of plasma protein binding on elimination of tauracholate by isolated perfused rat liver: comparison of venous equilibrium, undistributed and distributed sinusoidal, and dispersion models. J. Pharmacokin. Biopharm. 16: 377.CrossRefGoogle Scholar
  59. Smith, D.J., Grossbard, M., Gordon, E.R., Boyer, J.L., 1987. Tauracholate uptake by isolated skate hepatocytes: effect of albumin. Am. J. Physiol. 252: G479.PubMedGoogle Scholar
  60. Stremmel, W., Potter, B.J., Berk, P.D., 1983. Studies of albumin binding to rat liver plasma membranes. Implications for the albumin receptor hypothesis. Biochim. Biophys. Acta. 756: 20.PubMedCrossRefGoogle Scholar
  61. Tsao, S.C., Sugiyama, Y., Sawada, Y., Iga, T., Hanano, M., 1988. Kinetic analysis of albumin-mediated uptake of warfarin by perfused rat liver. J. Pharmacokin. Biopharm. 16: 165.CrossRefGoogle Scholar
  62. Tsao, S.C., Sugiyama, Y., Sawada, Y., Nagase, S., Iga, T., Hanano, M., 1986. Effect of albumin on hepatic uptalce of warfarin in normal and analbuminemic mutant rats: analysis by multiple indicator dilution methoch J. “Pharmacokin. Biopharm. 14: 51.CrossRefGoogle Scholar
  63. van der Sluijs, P., Postema, B., Meijer, D.K.F., 1987. Lactosylation of albumin reduces uptake rates of dibromosulfophthalein in perfused rat liver and dissociation rate from albumin in vitro. Hepatology 7: 688.PubMedCrossRefGoogle Scholar
  64. Weisiger, R., Gollan, J., Ockner, R., 1981. Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin bound substances. Science 211: 1048.PubMedCrossRefGoogle Scholar
  65. Weisiger, R.A., 1985. 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.CrossRefGoogle Scholar
  66. Weisiger, R.A., 1986. Non-equilibrium drug binding and hepatic drug removal. In: “Symposia Medica Hoechst, Volume 20: Protein binding and drug transport” ( J.-P. Tillement and E. Lindenlaub, eds.). Schattauer Verlag, New York.Google Scholar
  67. Weisiger, R.A., Zacks, C.M., Smith, N.D., Boyer, J.L., 1984. Effect of albumin binding on extraction of sulfobromophthalein by perfused elasmobranch liver: evidence for dissociation-limited uptake. Hepatology 4: 492.PubMedCrossRefGoogle Scholar
  68. Wen, C.Y., Fan, L.T., 1985. “Models for Flow Systems and Chemical Reactors”. Marcel Dekker, New York.Google Scholar
  69. Wolkoff, A.W., 1987. The role of an albumin receptor in hepatic organic anion uptake: the controversy continues. Hepatology 7: 777.PubMedCrossRefGoogle Scholar
  70. Xu, X., Pang, K.S., 1989. Hepatic modeling of metabolite kinetics in sequential and parallel pathways: salicylamide and gentisamide metabolism in perfused rat liver. J. Pharmacokin. Biopharm. 17: 645.CrossRefGoogle Scholar
  71. Yano, Y., Yamaoka, K., Aoyama, Y. Tanaka, H.,1989. Two-compartment dispersion model for analysis of organ perfusion system of drugs by Fast Inverse Laplace Transform (FILT). J. Pharmacokin. Biopharm. 17: 179.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Malcolm Rowland
    • 1
  • Allan M. Evans
    • 1
  1. 1.Department of PharmacyUniversity of ManchesterManchesterUK

Personalised recommendations