Clinical Pharmacokinetics

, Volume 21, Issue 1, pp 42–69

Clinical Pharmacokinetics in Patients with Liver Disease

  • Allan J. McLean
  • Denis J. Morgan
Review Article Clinical Pharmacokinetics and Disease Processes


From considerations of hepatic physiology and pathology coupled with pharmacokinetic principles, it appears that altered drug elimination in liver disease may result from the following mechanisms: reduction in absolute cell mass, in cellular enzyme content and/or activity, in portal vein perfusion due to extrahepatic/intrahepatic shunting, or of portal perfusion of hepatocyte mass due to decreased portal flow or sinusoidal perfusion; increase in arterial perfusion relative to portal perfusion; preferential perfusion of the sinusoidal midzone and terminal zones by arterioles; potential for direct mixing of arterial blood within the space of Disse; reduced exchange across the endothelial lining; and impaired diffusion within the space of Disse.

In general, oxidative drug metabolism is impaired in liver disease and the degree of impairment of oxidisation differs between drugs but correlates best with the degree of sinusoidal capillarisation, i.e. the degree of access of the drug from the sinusoid to the hepatocyte. Drug conjugation appears to be relatively unaffected by liver disease, whereas elimination by biliary excretion correlates best with the degree of intrahepatic shunting and not with sinusoidal capillarisation. As the latter should impair hepatocyte access of all compounds similarly, a potentially important mechanism could be impaired access of oxygen to hepatocytes as oxidative metabolism is much more sensitive to oxygen supply than are conjugation or biliary excretion. This suggests a potentially important therapeutic role for agents which increase the hepatic oxygen supply.

Useful adjunctive strategies may also derive from the oxygen limitation hypothesis. Anaemia should be targeted as a critically important variable, as should oxygen-carrying capacity, i.e. modification of the smoking habit. Additionally, enzyme inducers such as barbiturates may be used if overriding hypoxic constraints are removed by oxygen supplementation. Agents likely to seriously compromise arterial perfusion of the hepatic vascular bed should be avoided, e.g. those causing postural hypotension or vasospasm. Vasodilators can be used to actively promote arterial perfusion.

While the effect of liver disease on drug handling is highly variable and difficult to predict, there are well recognised principles for modifying dosage. These include halving the dose of drugs given systemically (or of low clearance drugs given orally) and a 50 to 90% reduction in the dose of drugs with a high hepatic clearance given orally. Changes in the pharmacodynamic effects of drugs (either alone or in addition to pharmacokinetic changes) can also be profound, and awareness of this possibility should be increased.


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  1. Acocella G, Bonollo L, Garimoldi M, Mainardi M, Tenconi LT, et al. Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease. Gut 13: 47–53, 1972PubMedCrossRefGoogle Scholar
  2. Aguirre C, Calvo R, Rodriguez-Sasiain JM. Serum protein binding of penbutolol in patients with hepatic cirrhosis. International Journal of Clinical Pharmacology, Therapy and Toxicology 26: 566–569, 1988Google Scholar
  3. Andreasen PB, Hutters L. Paracetamol (acetaminophen) clearance in patients with cirrhosis of the liver. Acta Medica Scandinavica (Suppl. 624): 99–105, 1979Google Scholar
  4. Angus PW, Mihaly GW, Morgan DJ, Smallwood RA. Oxygen dependence of omeprazole clearance and sulphone and sulphide metabolite formation in the isolated perfused rat liver. Journal of Pharmacology and Therapeutics 250: 1043–1047, 1989aGoogle Scholar
  5. Angus PW, Mihaly GW, Morgan DJ, Smallwood RA. Oxygen dependence of salbutamol elimination by the isolated perfused rat liver. Biochemical Pharmacology 38: 1443–1449, 1989bPubMedCrossRefGoogle Scholar
  6. Aw TK, Jones DP. Secondary bioenergetic hypoxia. Inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low O2 concentration. Journal of Biological Chemistry 219: 8997–9004, 1982Google Scholar
  7. Babbs CB, Haboubi NY, Mellor JM, Smith A, Rowan BP, et al. Endothelial cell transformation in primary biliary cirrhosis: A morphological and biochemical study. Hepatology 11: 723–729, 1990PubMedCrossRefGoogle Scholar
  8. Bakti G, Fisch HU, Karlaganis G, Minder C, Bircher J. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology 7: 629–638, 1987PubMedCrossRefGoogle Scholar
  9. Ballett F. Hepatic circulation: potential for therapeutic intervention. Pharmacology and Therapeutics 47: 281–328, 1990CrossRefGoogle Scholar
  10. Barbare JC, Poupon RE, Jaillon P, Prod’homme S, Darnis F, et al. Intrinsic hepatic clearance and Child-Turcotte classification for assessment of liver function in cirrhosis. Journal of Hepatology 1: 253–259, 1985PubMedCrossRefGoogle Scholar
  11. Barre J, Mallet A, Rosenbaum J, Deforges L, Houin G, et al. Pharmacokinetics of erythromycin in patients with severe cirrhosis. Respective influence of decreased serum binding and impaired liver metabolic capacity. British Journal of Clinical Pharmacology 23: 753–757, 1987PubMedCrossRefGoogle Scholar
  12. Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clinical Pharmacokinetics 15: 396–420, 1988PubMedCrossRefGoogle Scholar
  13. Benson GD. Acetaminophen in chronic liver disease. Clinical Pharmacology and Therapeutics 33: 95–101, 1983PubMedCrossRefGoogle Scholar
  14. Bergstrand RH, Wang T, Roden DM, Avant GR, Sutton WW, et al. Encainide disposition in patients with chronic cirrhosis. Clinical Pharmacology and Therapeutics 40: 148–154, 1986PubMedCrossRefGoogle Scholar
  15. Biou D, Konan D, Feger J, Agneray J, Leroy Y, et al. Alterations in the carbohydrate moiety of alpha-1-acid glycoprotein purified from human cirrhotic ascitic fluid. Biochimica et Biophysica Acta 912: 308–312, 1987CrossRefGoogle Scholar
  16. Birnie GG, McColl KEL, Thompson GG, Moore MR, Goldberg A, et al. Antipyrine metabolism in acute hepatic porphyria in relapse and remission. British Journal of Clinical Pharmacology 23: 358–361, 1987PubMedCrossRefGoogle Scholar
  17. Blaschke TF. Protein binding and kinetics of drugs in liver disease. Clinical Pharmacokinetics 2: 32–44, 1977PubMedCrossRefGoogle Scholar
  18. Blaschke TF, Rubin PC. Hepatic first-pass metabolism in liver disease. Clinical Pharmacokinetics 4: 423–432, 1979PubMedCrossRefGoogle Scholar
  19. Blei AT. Pharmacokinetic-hemodynamic interactions in cirrhosis. Seminars in Liver Disease 6: 299–308, 1986PubMedCrossRefGoogle Scholar
  20. Branch RA. Drugs as indicators of hepatic function. Hepatology 2: 97–105, 1982PubMedCrossRefGoogle Scholar
  21. Branch RA, Morgan MH, James J, Read AE. Intravenous administration of diazepam in patients with chronic liver disease. Gut 17: 975–983, 1976PubMedCrossRefGoogle Scholar
  22. Branch RA, Shand DG. Propranolol disposition in chronic liver disease: a physiological approach. Clinical Pharmacokinetics 1: 264–279, 1976PubMedCrossRefGoogle Scholar
  23. Breen KJ, Bury RW, Calder I, Desmond PV, Peters M, et al. A [14C]-phenacetin breath test to measure hepatic function in man. Hepatology 4: 47–52, 1984PubMedCrossRefGoogle Scholar
  24. Brodie MJ, Boobis AR, Bulpitt CJ, Davies DS. Influence of liver disease and environmental factors on hepatic monoxygenase activity in vitro. European Journal of Clinical Pharmacology 20: 39–46, 1981PubMedCrossRefGoogle Scholar
  25. Brody DH, Leichter L. Clearance tests of liver function. Medical Clinics of North America 63: 621–630, 1979PubMedGoogle Scholar
  26. Brosen K. Recent developments in hepatic drug oxidation. Implications for clinical pharmacokinetics. Clinical Pharmacokinetics 18: 220–239, 1990PubMedCrossRefGoogle Scholar
  27. Brunner G, von Bergmann K, Hacker W, von Mollendorff E. Comparison of diuretic effects and pharmacokinetics of torasemide and furosemide after a single oral dose in patients with hydropically decompensated cirrhosis of the liver. Arzneimittel-Forschung 38: 176–179, 1988PubMedGoogle Scholar
  28. Butterworth RF, Lavoie J, Giguere JF, Pomier-Layrargues G. Affinities and densities of high affinity [3H] muscimol (GABAA) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 8: 1084–1088, 1988PubMedCrossRefGoogle Scholar
  29. Byrne AJ, Morgan DJ, Harrison PM, McLean AJ. Variation in hepatic extraction rate with unbound drug fraction: discrimination between models of hepatic drug elimination. Journal of Pharmaceutical Sciences 74: 205–207, 1985PubMedCrossRefGoogle Scholar
  30. Caesar J, Shaldon S, Chiandussi L, Guevara L, Sherlock S. The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clinical Science 21: 43–57, 1961PubMedGoogle Scholar
  31. Campra JL, Reynolds TB. The hepatic circulation. In Arias et al. (Eds) The liver: biology and pathobiology, pp. 627–646, Raven Press, New York, 1982Google Scholar
  32. Cantrill E, Murray M, Mehta I, Farrell GC. Downregulation of the male-specific hepatic microsomal steroid 16a-hydroxylose, cytochrome P-450UT-A, in rats with portal bypass. Relevance to estradiol accumulation and impaired drug metabolism in hepatic cirrhosis. Journal of Clinical Investigation 83: 1211–1216, 1989PubMedCrossRefGoogle Scholar
  33. Caujolle B, Ballet F, Poupon R. Relationships among beta-adrenergic blockade, propranolol concentration, and liver function in patients with cirrhosis. Scandinavian Journal of Gastroenterology 23: 925–930, 1988PubMedCrossRefGoogle Scholar
  34. Cello JP, Øie S. Cimetidine disposition in patients with Laennec’s cirrhosis during multiple dosing therapy. European Journal of Clinical Pharmacology 25: 223–229, 1983PubMedCrossRefGoogle Scholar
  35. Cherrick GR, Stein SW, Leevy CM, Davidson CS. Indocyanine green: observations on its physical properties, plasma decay, and hepatic extraction. Journal of Clinical Investigation 39: 592–600, 1960PubMedCrossRefGoogle Scholar
  36. Colli A, Buccino G, Cocciolo M, Parravicini R, Scaltrino G. Disposition of a flow-limited drug (lidocaine) and a metabolic capacity-limited drug (theophylline) in liver cirrhosis. Clinical Pharmacology and Therapeutics 44: 642–649, 1988PubMedCrossRefGoogle Scholar
  37. Crotty B, Watson KJR, Desmond PV, Mashford ML, Wood LJ, et al. Hepatic extraction of morphine is impaired in cirrhosis. European Journal of Clinical Pharmacology 36: 501–506, 1989PubMedCrossRefGoogle Scholar
  38. Daneshmend TK, Homeida M, Kaye CM, Elamin AA, Roberts CJC. Disposition of oral metronidazole in hepatic cirrhosis and in hepatosplenic schistosomiasis in hepatic cirrhosis and in hepatosplenic schistosomiasis. Gut 23: 807–813, 1982PubMedCrossRefGoogle Scholar
  39. Dao MT, VIlleneuve J-P. Kinetics and dynamics of triamterene at steady-state in patients with cirrhosis. Clinical and Investigative Medicine 11: 6–9, 1988PubMedGoogle Scholar
  40. Davey PG. Pharmacokinetics in liver disease. Journal of Antimicrobial Chemotherapy 21: 1–8, 1988PubMedCrossRefGoogle Scholar
  41. Desmond PV, Patwardhan RV, Johnson RF, Schenker S. Impaired elimination of caffeine in cirrhosis. Digestive Diseases and Science 25: 193–197, 1980CrossRefGoogle Scholar
  42. Dunn MA, Kamal R. Hepatic schistosomiasis. Hepatology 1: 653–661, 1981PubMedCrossRefGoogle Scholar
  43. Du Souich P, Erill S. Metabolism of procainamide and p-aminobenzoic acid in patients with chronic liver disease. Clinical Pharmacology and Therapeutics 22: 588–595, 1977PubMedGoogle Scholar
  44. Echizen H, Ishizaki T. Superiority of disease-specific over conventional formula in predicting creatinine clearance from serum creatinine in patients with liver cirrhosis. Therapeutic Drug Monitoring 10: 369–375, 1988PubMedCrossRefGoogle Scholar
  45. Erlinger S. What is cholestasis in 1985? Journal of Hepatology 1: 687–693, 1985PubMedCrossRefGoogle Scholar
  46. Farrell GC, Cooksley WGE, Powell LW. Drug metabolism in liver disease: activity of hepatic microsomal metabolising enzymes. Clinical Pharmacology and Therapeutics 26: 483–492, 1979PubMedGoogle Scholar
  47. Farrell GC, Koltai A, Murray M. Source of raised serum estrogens in male rats with portal bypass. Journal of Clinical Investigation 81: 221–228, 1988PubMedCrossRefGoogle Scholar
  48. Farrell GC, Zaluzny L. Portal vein ligation selectively lowers hepatic cytochrome P450 levels in rats. Gastroenterology 85: 275–282, 1983PubMedGoogle Scholar
  49. Forrest JAH, Andriaenssens P, Finlayson NDC, Prescott LF. Paracetamol metabolism in chronic liver disease. European Journal of Clinical Pharmacology 15: 427–431, 1979PubMedCrossRefGoogle Scholar
  50. Forrest JAH, Finlayson NDC, Adjepon-Yamoah KK, Prescott LF. Antipyrine, paracetamol and lignocaine elimination in chronic liver disease. British Medical Journal 1: 1384–1387, 1977PubMedCrossRefGoogle Scholar
  51. Frost RW, Lettieri JT, Krol G, Shamblen EC, Lesseter KL. The effect of cirrhosis on the steady-state pharmacokinetics of oral ciproflaxin. Clinical Pharmacology and Therapeutics 45: 608–616, 1989PubMedCrossRefGoogle Scholar
  52. Fuller R, Hoppel C, Ingalls ST. Furosemide kinetics in patients with hepatic cirrhosis with ascites. Clinical Pharmacology and Therapeutics 30: 461–467, 1981PubMedCrossRefGoogle Scholar
  53. Gengo FM, Fagan SC, Krol G, Bernhard H. Nimodipine disposition and haemodynamic effects in patients with cirrhosis and age-matched controls. British Journal of Clinical Pharmacology 23: 46–53, 1987CrossRefGoogle Scholar
  54. Gerbes AL, Remien J, Jungst D, Sauerbruch Y, Paumgartner G. Evidence for down-regulation of beta-2-adrenoceptors in cirrhotic patients with severe ascites. Lancet 1: 1409–1411, 1986PubMedCrossRefGoogle Scholar
  55. Ghabrial H, Desmond PV, Watson KJR, Gijsbers AJ, Horman PJ, et al. The effects of age and chronic liver disease on the elimination of temazepam. European Journal of Clinical Pharmacology 30: 93–97, 1986PubMedCrossRefGoogle Scholar
  56. Giacomini KM, Giacomini JC, Gibson TP, Levy G. Propoxyphene and norpropoxyphene plasma concentrations after oral propoxyphene in cirrhotic patients with and without surgically constructed portacaval shunt. Clinical Pharmacology and Therapeutics 28: 417–424, 1980PubMedCrossRefGoogle Scholar
  57. Gonzalez FJ. Molecular genetics of the P-450 superfamily. Pharmacology and Therapeutics 45: 1–38, 1990PubMedCrossRefGoogle Scholar
  58. Gonzalez G, Aransibia A, Rivas MI, Caro P, Antezana C. Pharmacokinetics of frusemide in patients with hepatic cirrhosis. European Journal of Clinical Pharmacology 22: 315–320, 1982PubMedCrossRefGoogle Scholar
  59. Goresky CA. A linear method for determining liver sinusoidal and extracellular volume. American Journal of Physiology 204: 626–640, 1963PubMedGoogle Scholar
  60. Goresky CA, Bach GG, Nadeau BE. On the uptake of material by the intact liver: the transport and net removal of galactose. Journal of Clinical Investigation 52: 991–1009, 1973PubMedCrossRefGoogle Scholar
  61. Goresky CA, Ziegler WH, Bach GG. Capillary exchange modelling. Barrier-limited and flow-limited distribution. Circulation Research 27: 739–764, 1970PubMedCrossRefGoogle Scholar
  62. Grahnen A, Jameson S, Loof L, Tyllstrom J, Lindstrom B. Pharmacokinetics of cimetidine in advanced cirrhosis. European Journal of Clinical Pharmacology 26: 347–355, 1984PubMedCrossRefGoogle Scholar
  63. Greenway CV, Stark RD. Hepatic vascular bed. Physiological Reviews 51: 23–65, 1971PubMedGoogle Scholar
  64. Gross JB, Reichen J, Zeltner TB, Zimmermann A. The evolution of changes in quantitative liver function tests in a rat model of biliary cirrhosis: correlation with morphometric measurement of hepatocyte mass. Hepatology 7: 457–463, 1987PubMedCrossRefGoogle Scholar
  65. Groszmann R, Kotelanski B, Cohn JN, Khatri IM. Quantitation of portasystemic shunting from the splenic and mesenteric beds in alcoholic liver disease. American Journal of Medicine 53: 715–722, 1972PubMedCrossRefGoogle Scholar
  66. Groszmann RJ, Kravetz O, Paryzow O. Arteriovenous (AV) shunting in the liver. Gastroenterolopy 70: 983, 1976Google Scholar
  67. Groszmann RJ, Kravetz O, Paryzow O. Intrahepatic arteriovenous shunting in cirrhosis of the liver. Gastroenterology 73: 201–204, 1977PubMedGoogle Scholar
  68. Guechot J, Loric S, Vaubourdolle M, Chretien Y, Giboudeau J, et al. Effect of protein binding on testosterone extraction by human cirrhotic liver: evidence for a dissociation-limited uptake. Journal of Clinical Endocrinology and Metabolism 69: 200–203, 1989PubMedCrossRefGoogle Scholar
  69. Guengerich FP. Characterization of human microsomal cytochrome P-450 enzymes. Annual Review of Pharmacology and Toxicology 29: 241–264, 1989PubMedCrossRefGoogle Scholar
  70. Gugler R, Muller-Liebenau B, Somogyi A. Altered disposition of cimetidine in liver cirrhotic patients. British Journal of Clinical Pharmacology 14: 421–429, 1982PubMedCrossRefGoogle Scholar
  71. Hasselstrom J, Eriksson S, Persson A, Rane A, Svensson JO, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. British Journal of Clinical Pharmacology 29: 289–297, 1990PubMedCrossRefGoogle Scholar
  72. Heinzow B, Corbett H, Constantinides S, Bourne R, McLean AJ. Interaction between oral hydralazine and propranolol I. Changes in absorption, presystemic clearance and splanchnic blood flow. Journal of Pharmacology and Experimental Therapeutics 229: 509–514, 1984PubMedGoogle Scholar
  73. Henderson JM, Kutner MH, Bain RP. First-order clearance of plasma galactose: the effect of liver disease. Gastroenterology 83: 1090–1096, 1982PubMedGoogle Scholar
  74. Hepner GW, Vesell ES. Assessment of aminopyrine metabolism in man after administration of 14C-aminopyrine. Effects of phenobarbital, disulfram and portal cirrhosis. New England Journal of Medicine 291: 1384–1388, 1974PubMedCrossRefGoogle Scholar
  75. Hepner GW, Vesell ES, Lipton A, Harvey HA, Wilkinson GR, et al. Disposition of aminopyrine, antipyrine, diazepam and indocyanine green in patients with liver disease or on anticonvulsant drug therapy: diazepam breath test and correlations in drug elimination. Journal of Laboratory and Clinical Medicine 90: 440–456, 1977PubMedGoogle Scholar
  76. Hoefs J, Sakimura I, Reynolds T. Direct measurement of intrahepatic shunting by the portal vein injection of mirospheres. Gastroenterology 75: 968, 1978Google Scholar
  77. Holazo AO, Chen SS, McMahon FG, Ryan JR, Konikoff JJ, et al. The influence of liver dysfunction on the pharmacokinetics of carprofen. Journal of Clinical Pharmacology 25: 109–114, 1985PubMedGoogle Scholar
  78. Holstege A, Staiger M, Haag K, Gerok W. Correlation of caffeine elimination and Child’s classification in liver cirrhosis. Klinische Wochenschrift 67: 6–15, 1989PubMedCrossRefGoogle Scholar
  79. Homeida MMA, Ali HM, Arbab BMO, Harron DWG. Propranliver disease: can we expect to find a universal, quantitative marker of hepatic function? Hepatology 10: 893–895, 1989CrossRefGoogle Scholar
  80. Morgan MY, Stambuk D. Famotidine pharmacokinetics following oral and intravenous administration in patients with liver disease: results of a preliminary study. Postgraduate Medical Journal 62 (Suppl. 2): 29–37, 1986PubMedGoogle Scholar
  81. Morichau-Beauchant M, Hauin G, Mavier P, Alexandre C, Dhumeaux D. Pharmacokinetics and bioavailability of ranitidine in normal subjects and cirrhotic patients. Digestive Diseases and Sciences 31: 113–118, 1986PubMedCrossRefGoogle Scholar
  82. Murray M, Zaluzny L, Farrell GC. Drug metabolism in cirrhosis. Selective changes in cytochrome P450 isozymes in the cholinedeficient rat model. Biochemical Pharmacology 35: 1817–1824, 1986PubMedCrossRefGoogle Scholar
  83. Narang APS, Datta DV, Nath N, Mathur VS. Pharmacokinetic study of chloramphenicol in patients with liver disease. European Journal of Clinical Pharmacology 20: 479–483, 1981PubMedCrossRefGoogle Scholar
  84. Neal EA, Meffin PJ, Gregory PB, Blaschke TF. Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 77: 96–102, 1979PubMedGoogle Scholar
  85. Ochs HR, Greenblatt DJ, Verburg-Ochs B, Matlis R. Temazepam clearance unaltered in cirrhosis. American Journal of Gastroenterology 81: 80–84, 1986PubMedGoogle Scholar
  86. Oellerich M, Burdelski M, Lautz H-U, Schultz M, Schmidt F-W, et al. Lidocaine metabolite formation as a measure of liver function in patients with cirrhosis. Therapeutic Drug Monitoring 12: 219–226, 1990PubMedCrossRefGoogle Scholar
  87. Ohkubo H, Okuda K, Iida S, Ohnishi K, Ikawa S, et al. Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology 86: 514–520, 1984PubMedGoogle Scholar
  88. Ohnishi A, Tsuboi Y, Ishizaki T, Kubota K, Ohno T, et al. Kinetics and dynamics of enalapril in patients with liver cirrhosis. Clinical Pharmacology and Therapeutics 45: 657–665, 1989PubMedCrossRefGoogle Scholar
  89. Pacifici GM, Viana A, Franchi M, Santerini S, Temellini A, et al. Conjugation pathways in liver disease. British Journal of Clinical Pharmacology 30: 427–435, 1990PubMedCrossRefGoogle Scholar
  90. Pang KS, Rowland M. Hepatic clearance of drugs: 1. Theoretical considerations of a ‘well-stirred’ model and a ‘parallel’ 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
  91. Papadakis MA, Arief AI. Unpredictability of clinical evaluation of renal function in cirrhosis. American Journal of Medicine 82: 945–952, 1987PubMedCrossRefGoogle Scholar
  92. Papper S. Hepatorenal syndrome. In Epstein (Ed.) The kidney in liver disease, 2nd ed., pp. 87–106, Elsevier Biomedical, New York, 1983Google Scholar
  93. Patwardhan RV, Johnson RF, Hoyumpa A, Sheenan JJ, Desmond PV, et al. Normal metabolism of morphine in cirrhosis. Gastroenterology 81: 1006–1011, 1981PubMedGoogle Scholar
  94. Pedersen LE, Bonde J, Graudal NA, Backer NV, Hansen JES, et al. Quantitative and qualitative binding characteristics of disopyramide in serum from patients with decreased renal and hepatic function. British Journal of Clinical Pharmacology 23: 41–46, 1987PubMedCrossRefGoogle Scholar
  95. Pentikainen PJ, Hietakorpi S, Halinen MO, Lampinen LM. Cirrhosis of the liver markedly impairs the elimination of mexiletine. European Journal of Clinical Pharmacology 30: 83–88, 1986PubMedCrossRefGoogle Scholar
  96. Pentikainen PJ, Valisalmi L, Himberg JJ, Crevoisier C. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. Journal of Clinical Pharmacology 29: 272–277, 1989PubMedGoogle Scholar
  97. Pessayre D, Lebrec D, Descatoire V, Peignoux M, Benhamou J-P. Mechanism for reduced drug clearance in patients with cirrhosis. Gastroenterology 74: 566–571, 1978PubMedGoogle Scholar
  98. Plourde V, Gascon-Barré M, Coulombe PA, Vallires S, Huet P-M. Hepatic handling of vitamin D3 in micronodular cirrhosis: a structure-function study in the rat. Journal of Bone and Mineral Research 3: 461–471, 1988PubMedCrossRefGoogle Scholar
  99. Pomier-Layrargues G, Giguere JF, Lavoie J, Willems B, Butterworth RF. Pharmacokinetics of benzodiazepine antagonist Ro15-1788 in cirrhotic patients with moderate or severe liver dysfunction. Hepatology 10: 969–972, 1989PubMedCrossRefGoogle Scholar
  100. Pomier-Layrargues G, Huet PM, Villeneuve JP, Marleau D. Effect of portacaval shunt on drug disposition in patients with cirrhosis. Gastroenterology 91: 163–167, 1986PubMedGoogle Scholar
  101. Popper H, Elias H, Petty DE. Vascular pattern of the cirrhotic liver. American Journal of Clinical Pathology 22: 717–729, 1952PubMedGoogle Scholar
  102. Poupon RE, Poupon RY, Dumont M, Erlinger S, Hepatic storage and biliary transport maximum of taurocholate and tauro-cheno desoxycholate in the dog. European Journal of Clinical Investigation 6: 431–437, 1976PubMedCrossRefGoogle Scholar
  103. Poupon RY, Poupon RE, Lebrec D, Quernec LL, Darnis F. Mechanisms for reduced hepatic clearance and elevated plasma levels of bile acids in cirrhosis: a study in patients with an end-to-side portacaval shunt. Gastroenterology 80: 1438–1444, 1981PubMedGoogle Scholar
  104. Ramond M-J, Comoy E, Lebrec D. Alterations in isoprenaline sensitivity in patients with cirrhosis: evidence of abnormality of the sympathetic nervous activity. British Journal of Clinical Pharmacology 21: 191–196, 1986PubMedCrossRefGoogle Scholar
  105. Ramzan IM, Yasuhara M, Levy G. Kinetics of drug action in disease states: XIX. Effect of experimental liver disease on the neurotoxicity of theophylline in rats. Journal of Pharmacology and Experimental Therapeutics 241: 236–238, 1987PubMedGoogle Scholar
  106. Reichen J. Hepatic spaces and transport in the liver. In Petzinger et al. (Eds) Hepatic transport in organic substances, pp. 45–56, Springer-Verlag, Berlin 1989CrossRefGoogle Scholar
  107. Reichen J. Liver function and pharmacological considerations in pathogenesis and treatment of portal hypertension. Hepatology 11: 1066–1078, 1990PubMedCrossRefGoogle Scholar
  108. Reichen J, Arts B, Schafroth U, Zimmerman A, Zeltner T, et al. Aminopyrine N-demethylation by rats with liver cirrhosis: evidence for the intact cell hypothesis. A morphometric-functional study. Gastroenterology 93: 719–726, 1987aPubMedGoogle Scholar
  109. Reichen J, Egger B, Ohara N, Zeltner T, Zysset T, et al. Determinants of heptic function in liver cirrhosis in the rat: multivariate analysis. Journal of Clinical Investigation 82: 2069–2076, 1988PubMedCrossRefGoogle Scholar
  110. Reichen J, Hoilien C, Le M, Jones RH. Decreased uptake of taurocholate and ouabain by hepatocytes isolated from cirrhotic rat liver. Hepatology 7: 67–70, 1987bPubMedCrossRefGoogle Scholar
  111. Reichen J, Le M. Sinusoidal capillarization is more important than intrahepatic shunting to explain decreased propranolol clearance in liver cirrhotic rats. Abstract. Gastroenterology 84: 1283, 1983Google Scholar
  112. Reichen J, Le M. Verapamil favourably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. Journal of Clinical Investigation 78: 448–455, 1986PubMedCrossRefGoogle Scholar
  113. Reichen J, Simon FR. Cholestasis. In Arias et al. (Eds) The liver, biology and pathobiology, pp. 785–800, Raven Press, New York, 1982Google Scholar
  114. Renner E, Weitholtz H, Huguenin P, Arnaud MJ, Preisig R. Caffeine: a model compound for measuring liver function. Hepatology 4: 38–46, 1984PubMedCrossRefGoogle Scholar
  115. Rothschild MA, Oratz M, Schreiber SS. Serum albumin. Hepatology 8: 385–401, 1988PubMedCrossRefGoogle Scholar
  116. Roughton FJW, Forster RE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. Journal of Applied Physiology 11: 290–302, 1957PubMedGoogle Scholar
  117. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications pp. 189–190, Lea & Febiger, Philadelphia, 1989Google Scholar
  118. Royer RJ, Royer-Morrot MJ, Paille F, Barrucand D, Schmitt J, et al. Tianeptine and its main metabolite. Pharmacokinetics in chronic alcoholism and cirrhosis. Clinical Pharmacokinetics 16: 186–191, 1989PubMedCrossRefGoogle Scholar
  119. Sakiyama R, Pardridge WM, Judd HL. Effects of human cirrhotic serum on oestradiol and testosterone transport into rat brain. Journal of Clinical Endocrinology and Metabolism 54: 1140–1144, 1982PubMedCrossRefGoogle Scholar
  120. Samson Y, Bernau J, Pappata S, Chatoix C, Baron JC, et al. Cerebral uptake of benzodiazepine measured by positron emission tomography in hepatic encephalopathy. New England Journal of Medicine 316: 414–415, 1987PubMedCrossRefGoogle Scholar
  121. Saudek F, Moravek J, Modr Z. Cefoperazone pharmacokinetics in patients with liver cirrhosis: a predictive value of the ujoviridin test. International Journal of Clinical Pharmacology, Therapy and Toxicology 27: 82–87, 1989Google Scholar
  122. Schafer DF, Fowler JM, Munson PJ, Thakur AK, Waggoner JG, et al. Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. Journal of Laboratory and Clinical Medicine 102: 870–880, 1983PubMedGoogle Scholar
  123. Schenker S, Bergstrom RF, Wolen RL, Lemberger L. Fluoxetine disposition and elimination in cirrhosis. Clinical Pharmacology and Therapeutics 44: 353–359, 1988PubMedCrossRefGoogle Scholar
  124. Schentag JJ, Cerra FB, Calleri G, Deglopper E, Rose JQ, et al. Age, disease and cimetidine disposition in healthy subjects and chronically ill patients. Clinical Pharmacology and Therapeutics 29: 737–743, 1981PubMedCrossRefGoogle Scholar
  125. Scott NR, Stambuk D, Chakraborty J, Marks V, Morgan MY. Caffeine clearance and biotransformation in patients with chronic liver disease. Clinical Science 74: 377–384, 1988PubMedGoogle Scholar
  126. Scott NR, Stambuk D, Chakraborty J, Marks V, Morgan MY. The pharmacokinetics of caffeine and its dimethylxanthine metabolites in patients with chronic liver disease. British Journal of Clinical Pharmacology 27: 205–213, 1989PubMedCrossRefGoogle Scholar
  127. Secor JW, Schenker S. Drug metabolism in patients with liver disease. In Stollerman (Ed.) Advances in internal medicine. Vol. 32, pp. 379–406, Year Book Medical Publishers, Chicago 1987Google Scholar
  128. Sherman IA, Pappas SC, Fisher MM. Hepatic microvascular changes associated with development of liver fibrosis and cirrhosis. American Journal of Physiology 258: H460–H465, 1990PubMedGoogle Scholar
  129. Shull HJ, Wilkinson GR, Johnson R, Schenker S. Normal dispersion of oxazepam in acute viral hepatitis and cirrhosis. Annals of Internal Medicine 84: 420–425, 1976PubMedGoogle Scholar
  130. 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, 1987PubMedCrossRefGoogle Scholar
  131. Smallwood RH, Mihaly GW, Smallwood RA, Morgan DJ. Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction. Journal of Pharmacokinetics and Biopharmaceutics 16: 529–542, 1988PubMedGoogle Scholar
  132. Smith IL, Ziemniak JA, Bernhard H, Eshelman FN, Martin LE, et al. Ranitidine disposition and systemic availability in hepatic cirrhosis. Clinical Pharmacology and Therapeutics 35: 487–494, 1984PubMedCrossRefGoogle Scholar
  133. Sonne J, Andreasen PB, Loft S, Dossing M, Andreasen F. Glucuronidation of oxazepam is not spared in patients with hepatic encephalopathy. Hepatology 11: 951–956, 1990PubMedCrossRefGoogle Scholar
  134. Sonne J, Poulsen HE, Dossing M, Larsen NE, Andreasen PB. Cimetidine clearance and bioavailability in hepatic cirrhosis. Clinical Pharmacology and Therapeutics 29: 191–197, 1981PubMedCrossRefGoogle Scholar
  135. Sotaniemi EA, Niemela O, Risteli L, Stenback F, Pelkonen O, et al. Fibrotic process and drug metabolism in alcoholic liver disease. Clinical Pharmacology and Therapeutics 40: 46–55, 1986PubMedCrossRefGoogle Scholar
  136. Spahn H, Reuter K, Mutschier E, Gerok W, Knauf H. Pharmacokinetics of amiloride in renal and hepatic disease. European Journal of Clinical Pharmacology 33: 493–498, 1987PubMedCrossRefGoogle Scholar
  137. Tillement JP, Lhoste F, Giudiccelli JF. Disease and drug protein binding. Clinical Pharmacokinetics 3: 144–154, 1978PubMedCrossRefGoogle Scholar
  138. Trouvin J-H, Farinotti R, Haberer J-P, Servin F, Chauvin M, et al. Pharmacokinetics of midazolam in anaesthetised cirrhotic patients. British Journal of Anaesthesia 60: 762–767, 1988PubMedCrossRefGoogle Scholar
  139. Tygstrup N. Determination of hepatic galactose elimination capacity after a single intravenous injection in man. Acta Physiologica Scandinavica 58: 162–172, 1963PubMedCrossRefGoogle Scholar
  140. Tygstrup N, Winkler K. Galactose blood clearance as a measure of hepatic blood flow. Clinical Science 17: 1–9, 1958PubMedGoogle Scholar
  141. van Harten J, van Brummelen P, Wilson JHP, Lodweijks MTM, Breimer DD. Nisoldipine: kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis and intravenous and oral administration. European Journal of Clinical Pharmacology 34: 387–394, 1988PubMedCrossRefGoogle Scholar
  142. Varin F, Huet PM. Hepatic microcirculation in the perfused cirrhotic rat liver. Journal of Clinical Investigation 76: 1904–1912, 1985PubMedCrossRefGoogle Scholar
  143. Verbeeck RK, Patwardhan RV, Villeneuve J-P, Wilkinson GR, Branch RA. Furosemide disposition in cirrhosis. Clinical Pharmacology and Therapeutics 31: 719–725, 1982PubMedCrossRefGoogle Scholar
  144. Vesell ES. The antipyrine test in clinical pharmacology: conceptions and misconceptions. Clinical Pharmacology and Therapeutics 26: 275–286, 1979PubMedGoogle Scholar
  145. Vesell ES, Page JG. Genetic control of drug levels in man. Science 161: 72–73, 1968PubMedCrossRefGoogle Scholar
  146. Villeneuve JP, Fortunet-Fouin H, Arsene D. Cimetidine kinetics and dynamics in patients with severe liver disease. Hepatology 3: 923–927, 1983PubMedCrossRefGoogle Scholar
  147. Villeneuve JP, Huet PM. Microcirculatory abnormalities in liver disease. Hepatology 7: 186–187, 1987PubMedCrossRefGoogle Scholar
  148. Villeneuve JP, Rocheleau F, Raymond G. Triamterene kinetics and dynamics in cirrhosis. Clincial Pharmacology and Therapeutics 35: 831–837, 1984CrossRefGoogle Scholar
  149. Villeneuve JP, Thibeault MJ, Ampelas M, Fortunet-Fouin H, Lamarre L, et al. Drug disposition in patients with HBsAg-positive chronic liver disease. Digestive Diseases and Sciences 32: 710–714, 1987PubMedCrossRefGoogle Scholar
  150. Villeneuve JP, Verbeeck RK, Wilkinson GR, Branch RA. Furosemide kinetics and dynamics in patients with cirrhosis. Clinical Pharmacology and Therapeutics 40: 14–20, 1986PubMedCrossRefGoogle Scholar
  151. Vine JP, Caucanas JP, Cales P, Suduca JM, Voigt JJ, et al. Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis. Journal of Hepatology 7: 186–192, 1988CrossRefGoogle Scholar
  152. Watkins PB, Hamilton TA, Annesley TM, Ellis CN, Kolars JC, et al. The erythromycin breath test as a predictor of cyclosporin blood levels. Clinical Pharmacology and Therapeutics 48: 120–129, 1990PubMedCrossRefGoogle Scholar
  153. Watson RGP, Bastain W, Larkin KA, Hayes JR, McAinsh JA. A comparative pharmacokinetic study of conventional propranolol and a long acting preparation of propranolol in patients with cirrhosis and normal controls. British Journal of Clinical Pharmacology 24: 527–535, 1987PubMedCrossRefGoogle Scholar
  154. Watt G, White NJ, Padre L, Ritter W, Fernando MT, et al. Praziquantel pharmacokinetics and side effects in schistosoma japonicum-infested patients with liver disease. Journal of Infectious Diseases 157: 530–535, 1988PubMedCrossRefGoogle Scholar
  155. Wensing G, Ohnhaus EE, Hoensch HP. Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease. Clinical Pharmacology and Therapeutics 47: 693–705, 1990aGoogle Scholar
  156. Wensing G, Sabra R, Branch RA. Renal and systemic hemodynamics in experimental cirrhosis in rats: relation to hepatic function. Hepatology 12: 13–19, 1990bPubMedCrossRefGoogle Scholar
  157. Wiegard BD, Ketterer SG, Rapaport E. The use of indocyanine green for the evaluation of hepatic function and blood flow in man. American Journal of Digestive Diseases 5: 427–436, 1960CrossRefGoogle Scholar
  158. Wilkinson GR. Influence of hepatic disease on pharmacokinetics. In Evans et al. (Eds) Applied pharmacokinetics: principles of therapeutic drug monitoring, 2nd ed., pp. 116–138, Applied Therapeutics, Spokane 1986Google Scholar
  159. Wilkinson GR. Clearance approaches in pharmacology. Pharmacological Reviews 39: 1–47, 1987PubMedGoogle Scholar
  160. Williams RL, Blaschke TF, Meffin PJ, Melmon KL, Rowland M. Influence of viral hepatitis on the disposition of two compounds with high hepatic clearance: lidocaine and indocyanine green. Clinical Pharmacology and Therapeutics 20: 290–299, 1976PubMedGoogle Scholar
  161. Williams RL, Blaschke TF, Meffin PJ, Melmon KL, Rowland M. Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide. Clinical Pharmacology and Therapeutics 21: 301–309, 1977PubMedGoogle Scholar
  162. Williams RL, Upton RA, Cello JP, Jones RM, Blitstein M, et al. Naproxen disposition in patients with alcoholic cirrhosis. European Journal of Clinical Pharmacology 27: 291–296, 1984PubMedCrossRefGoogle Scholar
  163. Witassek F, Bircher J, Huguenin P, Preisig R. Abnormal glucuronidation of zomepirac in patients with cirrhosis of the liver. Hepatology 3: 415–422, 1983PubMedCrossRefGoogle Scholar
  164. Withrington PG, Richardson PDI. Hepatic hemodynamics and microcirculation. In Thurman et al. (Eds) Regulation of hepatic metabolism — intra and intercellular compartments, pp. 27–53, Plenum Press, New York, 1986Google Scholar
  165. Wood AJJ, Kornhauser DM, Wilkinson GR, Shand DG, Branch RA. The influence of cirrhosis on steady-state blood concentrations of unbound propranolol after oral administration. Clinical Pharmacokinetics 3: 478–487, 1978PubMedCrossRefGoogle Scholar
  166. Wood AJJ, Villeneuve JP, Branch RA, Rogers LW, Shand DG. Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology 76: 1358–1362, 1979PubMedGoogle Scholar
  167. Wood LJ, Massie D, McLean AJ, Dudley FJ. Renal sodium retention in cirrhosis: tubular site and relation to hepatic dysfunction. Hepatology 8: 831–836, 1988PubMedCrossRefGoogle Scholar
  168. Young CJ, Daneshmend TK, Roberts CJC. Effects of cirrhosis and aging in the elimination and bioavailability of ranitidine. Gut 23: 819–832, 1982PubMedCrossRefGoogle Scholar
  169. Zaki AEO, Ede RJ, Davis M, Williams R. Experimental studies of blood brain barrier permeability in acute hepatic failure. Hepatology 4: 359–363, 1984PubMedCrossRefGoogle Scholar
  170. Zeeh J, Lange H, Bosch J, Pohl S, Loesgen H, et al. Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology 95: 749–759, 1988PubMedGoogle Scholar
  171. Zeneroli ML. Hepatic encephalopathy. Experimental studies in a rat model of fulminant hepatic failure. Journal of Hepatology 1: 301–312, 1985PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Allan J. McLean
    • 1
    • 2
  • Denis J. Morgan
    • 1
    • 2
  1. 1.Clinical Pharmacology DepartmentAlfred HospitalMelbourneAustralia
  2. 2.Department of PharmaceuticsVictorian College of PharmacyMelbourneAustralia
  3. 3.Alfred HospitalPrahranAustralia

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