Advertisement

Clinical Pharmacokinetics

, Volume 18, Issue 1, pp 61–76 | Cite as

Clinical Significance of Pharmacokinetic Models of Hepatic Elimination

  • Denis J. Morgan
  • Richard A. Smallwood
Review Article Clinical Pharmacokinetic Concepts

Summary

Various pharmacokinetic models, both simple and complex, have been developed to describe the way in which the rate of hepatic elimination of drugs depends on hepatic blood flow, hepatic intrinsic clearance and unbound fraction of drug in blood. A model is necessary because it is not possible to measure the average blood concentration of drug within the liver, i.e. the concentration at the site of drug elimination. However, the predictions of these models can differ markedly for drugs of high hepatic clearance, especially with the oral route of administration. Investigations of the models have mostly involved studies with in vitro experimental preparations, such as isolated perfused livers. While such studies have advanced our understanding of the mechanism of hepatic uptake and elimination processes, the implications for clinical drug usage have been somewhat neglected.

Use of one of the available models is necessary for the assessment of the capacity of in vivo hepatic drug metabolism processes (i.e. hepatic intrinsic clearance) and for predicting the effect of increasing dose on blood concentrations of high clearance drugs exhibiting Michaelis-Menten elimination kinetics, especially those that undergo a nonlinear hepatic first-pass effect. Clinically significant differences between the models can occur under these circumstances. A model is also required for quantitative prediction of the effect on blood drug concentrations of changes in hepatic blood flow, hepatic intrinsic clearance or drug-protein binding in blood. It is in predicting these changes that differences of major clinical significance can occur between the models. The greatest differences are seen in predicting the effect for orally administered drugs of changes of hepatic blood flow on blood concentrations, and changes of protein binding on unbound blood concentrations of drug. These changes can result from disease processes, altered physiology (old age or pregnancy), food intake or concomitant administration of other drugs. A model is also required for determining the mechanism by which such clinical changes occur.

When considering these effects on hepatic elimination, it is essential to appreciate that the conclusions may depend markedly on the particular model chosen. Until more data on the applicability of the models are obtained in humans, the undistributed sinusoidal and venous equilibrium models, which represent the opposite extremes of behaviour among the available models, should both be used in assessing hepatic drug elimination.

Keywords

Propranolol Hepatic Blood Flow Hepatic Clearance Unbind Fraction Intrinsic Clearance 
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 AB, Bennett PN, Rowland M. Influence of route of hepatic administration on drug availability. Journal of Pharmacology and Experimental Therapeutics 230: 718–725, 1984PubMedGoogle Scholar
  2. Anderson JH, Anderson RC, Iben S. Hepatic uptake of propranolol. Journal of Pharmacology and Experimental Therapeutics 206: 172–180, 1978PubMedGoogle Scholar
  3. Barbare JC, Poupon RE, Jaillon P, Prod’homme A, Darnis F, et al. Intrinsic hepatic clearance and Child-Tucotte classification for assessment of liver function in cirrhosis. Journal of Hepatology 1: 253–259, 1985PubMedGoogle Scholar
  4. Bass L, Keiding S. Physiologically based models and strategic experiments in hepatic pharmacology. Biochemical Pharmacology 37: 1425–1431, 1988PubMedGoogle Scholar
  5. Bass L, Keiding S, Winkler K, Tygstrup N. Enzymatic elimination of substrates flowing through the intact liver. Journal of Theoretical Biology 61: 393–409, 1976PubMedGoogle Scholar
  6. Bass L, Roberts MS, Robinson PJ. On the relation between extended forms of the sinusoidal perfusion and the convection-dispersion models of hepatic elimination. Journal of Theoretical Biology 126: 457–482, 1987PubMedGoogle Scholar
  7. Bass L, Robinson P, Bracken AJ. Hepatic elimination of flowing substrates: the distributed model. Journal of Theoretical Biology 72: 161–184, 1978PubMedGoogle Scholar
  8. Bass L, Winkler K. A method of determining intrinsic hepatic clearance from the first-pass effect. Clinical and Experimental Pharmacology and Physiology 7: 339–343, 1980PubMedGoogle Scholar
  9. Bax NDS, Tucker GT, Lennard MS, Woods HF. The impairment of lignocaine clearance by propranolol — major contribution from enzyme inhibition. British Journal of Clinical Pharmacology 19: 597–603, 1985PubMedGoogle Scholar
  10. Blom A, Scaf AHJ, Meijer DKF. Hepatic drug transport in the rat. A comparison between isolated hepatocytes, the isolated perfused liver and the liver in vivo. Biochemical Pharmacology 31: 1553–1565, 1982PubMedGoogle Scholar
  11. Branch RA. Drugs as indicators of liver function. Hepatology 2: 97–105, 1982PubMedGoogle Scholar
  12. Branch RA, Shand DG. Propranolol disposition in chronic liver disease: a physiological approach. Clinical Pharmacokinetics 1: 264–279, 1976PubMedGoogle Scholar
  13. Brandt JL, Castleman L, Ruskin HD, Greenwald J, Kelly JH. The effect of oral protein and glucose feeding on splanchnic blood flow and oxygen utilization in normal and cirrhotic patients. Journal of Clinical Investigation 34: 1017–1025, 1955PubMedGoogle Scholar
  14. Byrne AJ, McNeil JJ, Harrison PM, Louis W, Tonkin AM, et al. Stable oral availability of sustained release propranolol when co-administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions. British Journal of Clinical Pharmacology 17: 45S–50s, 1984PubMedGoogle Scholar
  15. Chen EH, Gumucio JJ, Ho NH, Gumucio DL. Hepatocytes of zones 1 and 3 conjugate sulfobromophthalein with glutathione. Hepatology 4: 467–476, 1984PubMedGoogle Scholar
  16. Collins JM, Blake DA, Egner PG. Phenytoin metabolism in the rat: pharmacokinetic correlation between in vitro hepatic microsomal enzyme activity and in vivo elimination kinetics. Drug Metabolism and Disposition 6: 251–257, 1978PubMedGoogle Scholar
  17. Conrad KA, Byers JM, Finley PR, Burnham L. Lidocaine elimination: effects of metoprolol and of propranolol. Clinical Pharmacology and Therapeutics 33: 133–138, 1983PubMedGoogle Scholar
  18. D’Arcy PF, McElnay JC. Drug interactions involving the displacement of drugs from plasma protein and tissue binding sites. Pharmacology and Therapeutics 17: 211–220, 1982PubMedGoogle Scholar
  19. De Lannoy IAM, Pang KS. Presence of a diffusional barrier on metabolite pharmacokinetics: enalaprilat as a generated versus performed metabolite. Drug Metabolism and Disposition 14: 513–520, 1986PubMedGoogle Scholar
  20. Forker EL, Luxon BA. Hepatic transport kinetics and plasma disappearance curves: distributed modeling versus conventional approach. American Journal of Physiology 235: E648–E660, 1978PubMedGoogle Scholar
  21. Forker EL, Luxon BA. Lumpers vs distributers. Hepatology 5: 1236–1237, 1985PubMedGoogle Scholar
  22. George CF. Drug metabolism by the gastrointestinal mucosa. Clinical Pharmacokinetics 6: 259–274, 1981PubMedGoogle Scholar
  23. Gerber MC, Tejwani GA, Gerber N, Bianchine JR. Drug interactions with cimetidine: an update. Pharmacology and Therapeutics 27: 353–370, 1985PubMedGoogle Scholar
  24. Gillette JR. Factors affecting drug metabolism. Annals of the New York Academy of Sciences 179: 43–66, 1971PubMedGoogle Scholar
  25. Gillette JR, Pang KS. Theoretic aspects of pharmacokinetic drug interactions. Clinical Pharmacology and Therapeutics 22: 623–639, 1977PubMedGoogle Scholar
  26. Goresky CA, Bach GG, Nadeau BE. On the uptake of materials by the intact liver. The transport and net removal of galactose. Journal of Clinical Investigation 52: 991–1009, 1973PubMedGoogle Scholar
  27. Gray MR, Tarn YK. The series-compartment model for hepatic elimination. Drug Metabolism and Disposition 15, 27–31, 1987PubMedGoogle Scholar
  28. Greenway CV, Stark RD. Hepatic vascular bed. Physiological Reviews 51: 23–65, 1971PubMedGoogle Scholar
  29. Groothius GMM, Hardonk MJ, Keulemans KPT, Niewenhuis P, Meijer DKF. Autoradiographic and kinetic demonstration of acinar heterogeneity of taurocholate transport. American Journal of Physiology 243: G455–G462, 1982Google Scholar
  30. Gumucio JJ, Miller DL. Functional implications of liver cell heterogeneity. Gastroenterology 80: 393–403, 1981PubMedGoogle Scholar
  31. Gumucio JJ, Miller DL, Krauss MD, Zanolli CC. Transport of fluorescent compounds into hepatocytes and the resultant zonal labelling of the hepatic acinus in the rat. Gastroenterology 80: 639–646, 1981PubMedGoogle Scholar
  32. Hogstedt S, Lindberg B, Rane A. Increased oral clearance of metoprolol in pregnancy. European Journal of Clinical Pharmacology 24: 217–220, 1983PubMedGoogle Scholar
  33. Huet P, Lelorier J. Effects of smoking and chronic hepatitis B on lidocaine and indocyanine green kinetics. Clinical Pharmacology and Therapeutics 28: 208–215, 1980PubMedGoogle Scholar
  34. Huet P, Villeneuve J. Determinants of drug disposition in patients with cirrhosis. Hepatology 3: 913–918, 1983PubMedGoogle Scholar
  35. Jones AL, Hradek GT, Renston RH, Wong KY, Karlaganis G, et al. Autoradiographic evidence for hepatic lobular concentration gradient of bile acid derivative. American Journal of Physiology 238: G233–G237, 1980PubMedGoogle Scholar
  36. Kashiwagi T, Kimura K, Seumatsu T, Schichiri M, Kamada T, et al. Heterogeneous intrahepatic distribution of blood flow in humans. European Journal of Nuclear Medicine 6: 545–549, 1981PubMedGoogle Scholar
  37. Kawasaki S, Sugiyama Y, Iga T, Hanano M, Beppu T, et al. Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases. Clinical Pharmacology and Therapeutics 44: 217–224, 1988PubMedGoogle Scholar
  38. Keiding S. Hepatic elimination kinetics: the influence of hepatic blood flow on clearance determinations. Scandinavian Journal of Clinical and Laboratory Medicine 36: 113–118, 1976Google Scholar
  39. Keiding S. Hepatic clearance and liver blood flow. Journal of Hepatology 4: 393–398, 1987PubMedGoogle Scholar
  40. Keiding S, Andreasen PB. Hepatic clearance measurements and pharmacokinetics. Pharmacology 19: 105–110, 1979PubMedGoogle Scholar
  41. Kitani K. Hepatic drug metabolism in the elderly. Hepatology 6: 316–319, 1986PubMedGoogle Scholar
  42. Koo A, Liang IYS, Cheng KK. The terminal hepatic microcirculation in the rat. Quarterly Journal of Experimental Physiology 60: 261–266, 1975Google Scholar
  43. Kremer JMH, Wilting J, Janssen LHM. Drug binding to human α1-acid glycoprotein in health and disease. Phrmacological Reviews 40: 1–47, 1988Google Scholar
  44. Levitt MD, Levitt DG. Intrinsic hepatic clearance in cirrhosis. Gastroenterology 75: 346, 1978PubMedGoogle Scholar
  45. Loi C, Vestal RE. Drug metabolism in the elderly. Pharmacology and Therapeutics 36: 131–149, 1988PubMedGoogle Scholar
  46. MacKichan JJ. Protein binding drug displacement interactions: fact or fiction? Clinical Pharmacokinetics 16: 65–73, 1989PubMedGoogle Scholar
  47. Mayersohn M. Special pharmacokinetic considerations in the elderly. In Evans et al. (Eds) Applied pharmacokinetics. Principles of therapeutic drug monitoring, pp. 229–293, Applied Therapeutics Inc., Spokane, 1986Google Scholar
  48. McAinsh J, Baber NS, Holmes BF, Young J, Ellis SH. Bioavailability of sustained release propranolol formulations. Biopharmaceutics and Drug Disposition 2: 39–48, 1981Google Scholar
  49. McAinsh J, Baber NS, Smith R, Young J. Pharmacokinetic and pharmacodynamic studies with long-acting propranolol. British Journal of Clinical Pharmacology 6: 115–121, 1978PubMedGoogle Scholar
  50. McAinsh J, Gay MA. Theoretical Michaelis-Menten elimination model for propranolol. European Journal of Drug Metabolism and Pharmacokinetics 10: 241–245, 1985PubMedGoogle Scholar
  51. McLean A, du Souich P, Gibaldi M. Noninvasive approach to the estimation of total hepatic blood flow and shunting in chronic liver disease — a hypothesis. Clinical Pharmacology and Therapeutics 25: 161–166, 1979PubMedGoogle Scholar
  52. McLean AJ, Isbister C, Bobik A, Dudley FJ. Reduction of first-pass hepatic clearance of propranolol by food. Clinical Pharmacology and Therapeutics 30: 31–34, 1981PubMedGoogle Scholar
  53. McLean AJ, McNamara PJ, du Souich P, Gibaldi M, Lalka D. Food, splanchnic blood flow, and bioavailability of drugs subject to first-pass metabolism. Clinical Pharmacology and Therapeutics 24: 5–10, 1978PubMedGoogle Scholar
  54. McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction between oral propranolol and hydralazine. Clinical Pharmacology and Therapeutics 27: 726–732, 1980PubMedGoogle Scholar
  55. Melander A, Danielson K, Schersten B, Wahlin E. Enhancement of the bioavailability of propranolol and metoprolol by food. Clinical Pharmacology and Therapeutics 22: 108–112, 1977PubMedGoogle Scholar
  56. Melander A, Lalka D, McLean A. Influence of food on the presystemic metabolism of drugs. Pharmacology and Therapeutics 38: 253–267, 1988PubMedGoogle Scholar
  57. Melander A, McLean A. Influence of food intake on presystemic clearance of drugs. Clinical Pharmacokinetics 8: 286–296, 1983PubMedGoogle Scholar
  58. Miners JO, Attwood J, Birkett DJ. Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen’s metabolic pathways. Clinical Pharmacology and Therapeutics 35, 480–486, 1984PubMedGoogle Scholar
  59. Miners JO, Robson RA, Birkett DJ. Paracetamol metabolism in pregnancy. British Journal of Clinical Pharmacology 22: 359–362, 1986PubMedGoogle Scholar
  60. Mistry M, Houston JB. Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, nalaxone and buprenorphine. Drug Metabolism and Disposition 15: 710–717, 1987PubMedGoogle Scholar
  61. Mitani GM, Steinberg I, Lien EJ, Harrison EC, Elkayam U. The pharmacokinetics of antiarrhythmic agents in pregnancy and lactation. Clinical Pharmacokinetics 12: 253–291, 1987PubMedGoogle Scholar
  62. Modi MW, Hassett JM, Lalka D. Influence of posture on hepatic perfusion and the presystemic biotransformation of propranolol: simulation of the food effect. Clinical Pharmacology and Therapeutics 44: 268–274, 1988PubMedGoogle Scholar
  63. Morgan DJ, Jones DB, Smallwood RA. Modeling of substrate elimination by the liver: has the albumin receptor model superseded the well-stirred model? Hepatology 5: 1231–1235, 1985PubMedGoogle Scholar
  64. Mouelhi ME, Kauffman FC. Sublobular distribution of transferases and hydrolases associated with glucuronide, sulfate and glutathione conjugation in human liver. Hepatology 6: 450–456, 1986PubMedGoogle Scholar
  65. Mucklow JC. Environmental factors affecting drug metabolism. Pharmacology and Therapeutics 36: 105–117, 1988PubMedGoogle Scholar
  66. Munnell EW, Taylor HC. Liver blood flow in pregnancy — hepatic vein catheterization. Journal of Clinical Investigation 26: 952–956, 1947PubMedGoogle Scholar
  67. Nies AS, Shand DG, Wilkinson GR. Altered hepatic blood flow and drug disposition. Clinical Pharmacokinetics 1: 135–155, 1976PubMedGoogle Scholar
  68. Ochs HR, Carstens G, Greenblatt DJ. Reduction in lidocaine clearance during continuous infusion and by coadministration of propranolol. New England Journal of Medicine 303: 373–377, 1980PubMedGoogle Scholar
  69. Olanoff LS, Walle T, Cowart TD, Walle UK, Oexmann MJ, et al. Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis. Clinical Pharmacology and Therapeutics 40: 408–414, 1986PubMedGoogle Scholar
  70. Pang KS, Rowland M. 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 the hepatocellular enzymatic activity on hepatic drug clearance. Journal of Pharmacokinetics and Biopharmaceutics 5: 625–653, 1977PubMedGoogle Scholar
  71. Park BK, Breckenridge AM. Clinical implications of enzyme induction and enzyme inhibition. Clinical Pharmacokinetics 6: 1–24, 1981PubMedGoogle Scholar
  72. Paxton JW. Alpha1-acid glycoprotein and binding of basic drugs. Methods and Findings in Experimental and Clinical Pharmacology 5: 635–648, 1983PubMedGoogle Scholar
  73. Perucca E. Drug metabolism in pregnancy, infancy and childhood. Pharmacology and Therapeutics 34: 129–143, 1987PubMedGoogle Scholar
  74. Pessayre D, Lebrec D, Descatoire V, Peignoux M, Benhamou J. Mechanism for reduced drug clearance in patients with cirrhosis. Gastroenterology 74: 566–571, 1978PubMedGoogle Scholar
  75. Piafsky KM. Disease-induced changes in plasma binding of basic drugs. Clinical Pharmacokinetics 5: 246–262, 1980PubMedGoogle Scholar
  76. Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clinical Pharmacokinetics 9: 1–25, 1984PubMedGoogle Scholar
  77. Rane A, Wilkinson GR, Shand DG. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. Journal of Pharmacology and Experimental Therapeutics 200: 420–424, 1977PubMedGoogle Scholar
  78. Richardson PDI, Granger DN. Microcirculation of the liver and spleen. In Mortillaro NA (Ed.) The physiology and pharmacology of the microcirculation, pp. 95–131, Academic Press, London, 1984Google Scholar
  79. Roberts MS, Donaldson JD, Rowland M. 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. Journal of Pharmacokinetics and Biopharmaceutics 16, 41–83, 1988PubMedGoogle Scholar
  80. Roberts MS, Rowland M. A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations. Journal of Pharmacokinetics and Biopharmaceutics 14: 227–260, 1986aPubMedGoogle Scholar
  81. Roberts MS, Rowland M. A dispersion model of hepatic elimination: 2. Steady state considerations — influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity. Journal of Pharmacokinetics and Biopharmaceutics 14: 261–288, 1986bPubMedGoogle Scholar
  82. Roberts MS, Rowland M. Correlation between in-vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model. Journal of Pharmacy and Pharmacology 38: 177–181, 1986cPubMedGoogle Scholar
  83. Roberts RK, Schenker S. Clearly there is intrinsic value in intrinsic clearance. Hepatology 3: 1036–1038, 1983PubMedGoogle Scholar
  84. Robinson PJ, Bass L, Pond SM, Roberts MS, Wagner JG. Clinical applicability of current pharmacokinetic models: splanchnic elimination of 5-fluorouracil in cancer patients. Journal of Pharmacokinetics and Biopharmaceutics 16: 229–249, 1988PubMedGoogle Scholar
  85. Rollins DE, Alvan G, Bertilsson L, Gillette JR, Mellstrom B, et al. Individual differences in amitriptyline demethylation. Clinical Pharmacology and Therapeutics 28: 121–129, 1980PubMedGoogle Scholar
  86. Routledge PA. The plasma protein binding of basic drugs. British Journal of Clinical Pharmacology 22: 499–506, 1986PubMedGoogle Scholar
  87. Rowland M, Benet LZ, Graham GG. Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1: 123–136, 1973PubMedGoogle Scholar
  88. Sato H, Sugiyama Y, Miyauchi S, Sawada Y, Iga T, et al. A simulation study on the effect of a uniform diffusional barrier across hepatocytes on drug metabolism by evenly or unevenly distributed uni-enzyme in the liver. Journal of Pharmaceutical Sciences 75: 3–8, 1986PubMedGoogle Scholar
  89. Sawada Y, Sugiyama Y, Miyamoto Y, Iga T, Hanano M. Hepatic drug clearance model: comparison among the distributed, parallel-tube and well-stirred models. Chemical and Pharmaceutical Bulletin 33: 319–326, 1985Google Scholar
  90. Skak C, Keiding S. Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man. Liver 7: 155–162, 1987PubMedGoogle Scholar
  91. Smallwood RH, Morgan DJ, Mihaly GW, Jones DB, Smallwood RA. Effect of plasma protein binding on elimination of taurocholate by isolated perfused rat liver: comparison of venous equilibrium, undistributed and distributed sinusoidal, and dispersion models. Journal of Pharmacokinetics and Biopharmaceutics 16: 377–396, 1988PubMedGoogle Scholar
  92. St Hilaire RJ, Hradek GT, Jones AL. Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a highcapacity uptake system. Proceedings of the National Academy of Sciences of the United States of America 80: 3797–3801, 1983PubMedGoogle Scholar
  93. Straka RJ, Lalonde RL, Pieper JA, Bottorff MB, Mirvis DM. Nonlinear pharmacokinetics of unbound propranolol after oral administration. Journal of Pharmaceutical Sciences 76: 521–524, 1987PubMedGoogle Scholar
  94. Svensson CK, Edwards DJ, Mauriello PM, Barde SH, Foster AC, et al. Effect of food on hepatic blood flow: implications in the ‘food effect’ phenomenon. Clinical Pharmacology and Therapeutics 34: 316–323, 1983PubMedGoogle Scholar
  95. Svensson CK, Mauriello PM, Barde SH, Middleton E, Lalka D. Effect of carbohydrates on estimated hepatic blood flow. Clinical Pharmacology and Therapeutics 35: 660–665, 1984PubMedGoogle Scholar
  96. Svensson CK, Woodruff MN, Baxter JG, Lalka D. Free drug monitoring in clinical practice. Rationale and current status. Clinical Pharmacokinetics 11: 450–469, 1986PubMedGoogle Scholar
  97. Tucker GT, Bax NDS, Lennard MS, Alasady SAH, Bharaj HS, et al. Effects of beta-adrenoceptor antagonists on the pharmacokinetics of lignocaine. British Journal of Clinical Pharmacology 17: 21S–28S, 1984PubMedGoogle Scholar
  98. Vestal RE, Wood AJJ. Influence of age and smoking on drug kinetics in man. Studies using model compounds. Clinical Pharmacokinetics 5: 309–319, 1980PubMedGoogle Scholar
  99. Wagner JG. Predictability of verapamil steady-state plasma levels from single-dose data explained. Clinical Pharmacology and Therapeutics 36: 1–4, 1984PubMedGoogle Scholar
  100. Wagner JG. Propranolol: pooled Michaelis-Menten parameters and the effect of input rate on bioavailability. Clinical Pharmacology and Therapeutics 37: 481–487, 1985aPubMedGoogle Scholar
  101. Wagner JG. Comparison of nonlinear pharmacokinetic parameters estimated from the sinusoidal perfusion and venous equilibrium models. Biopharmaceutics and Drug Disposition 6: 23–31, 1985bGoogle Scholar
  102. Wagner JG. Modeling first-pass metabolism. In Pecile & Rescigno (Eds) Pharmacokinetics. Mathematical and statistical approaches to metabolism and distribution of chemicals and drugs, pp. 129–149, Plenum Press, New York, 1988aGoogle Scholar
  103. Wagner JG. Effect of first-pass Michaelis-Menten metabolism on performance of controlled release dosage forms. In Yacobi Halperin-Walega (Eds) Oral sustained release formulations: design and evaluation, pp. 95–124, 1988bGoogle Scholar
  104. Wagner JG, Antal EJ, Elvin AT, Gillespie WR, Pratt EA, et al. Theoretical decrease in systemic availability with decrease in input rate at steady-state for first-pass drugs. Biopharmaceutics and Drug Disposition 6: 341–343, 1985aGoogle Scholar
  105. Wagner JG, Szpunar GJ, Ferry JJ. Commentary: exact mathematical equivalence of the venous equilibration (‘parallel-tube’) model, and a specific two-compartment open model. Drug Metabolism and Dispersion 12: 385–388, 1984Google Scholar
  106. Wagner JG, Szpunar GJ, Ferry JJ. A nonlinear physiologic pharmacokinetic model: 1. Steady-state. Journal of Pharmacokinetics and Biopharmaceutics 13: 73–92, 1985bPubMedGoogle Scholar
  107. Weisiger RA. Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver. Proceedings of the National Academy of Sciences of the United States of America 82: 1563–1567, 1985PubMedGoogle Scholar
  108. Weisiger RA, Mendel CM, Cavalieri RR. The hepatic sinusoid is not well-stirred: estimation of the degree of axial mixing by analysis of lobular concentration gradients formed during uptake of thyroxine by the perfused rat liver. Journal of Pharmaceutical Sciences 75: 233–237, 1986PubMedGoogle Scholar
  109. Wilkinson GR. Influence of hepatic disease on pharmacokinetics. In Evans et al. (Eds) Applied pharmacokinetics. Principles of therapeutic drug monitoring, pp. 116–138, Applied Therapeutics Inc., Spokane, 1986Google Scholar
  110. Wilkinson GR. Clearance approaches in pharmacology. Pharmacological Reviews 39: 1–47, 1987PubMedGoogle Scholar
  111. Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390, 1975PubMedGoogle Scholar
  112. Williams RL, Mamelok RD. Hepatic disease and drug pharmacokinetics. Clinical Pharmacokinetics 5: 528–547, 1980PubMedGoogle Scholar
  113. Winkler K, Bass L, Keiding S, Tygstrup N. The effect of hepatic perfusion on the assessment of kinetic constants. In Lundqvist & Tygstrup (Eds) Regulation of hepatic metabolism, pp. 797–807, Munksgaard, Copenhagen, 1974Google Scholar
  114. Winkler K, Bass L, Keiding S, Tygstrup N. The physiologic basis for clearance measurements in hepatology. Scandinavian Journal of Gastroenterology 14: 439–448, 1979PubMedGoogle Scholar
  115. Winkler K, Keiding S, Tygstrup N. Clearance as a quantitative measure of liver function. In Paumgartner & Preisig (Eds) The liver. Quantitative aspects of structure and function, pp. 144–155, Karger, Basel, 1973Google Scholar
  116. Wood M. Plasma drug binding: implications for anesthesiologists. Anesthesia and Analgesia 65: 786–804, 1986PubMedGoogle Scholar

Copyright information

© ADIS Press Limited 1990

Authors and Affiliations

  • Denis J. Morgan
    • 1
    • 2
  • Richard A. Smallwood
    • 1
    • 2
  1. 1.Department of PharmaceuticsVictorian College of PharmacyMelbourneAustralia
  2. 2.Gastroenterology Unit, Department of MedicineAustin HospitalMelbourneAustralia

Personalised recommendations