Clinical Pharmacokinetics

, Volume 29, Issue 5, pp 370–391 | Cite as

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

An Update
  • Denis J. Morgan
  • Allan J. McLean
Review Article Clinical Pharmacokinetics in Special Populations

Summary

The effects of liver disease on pharmacokinetics and pharmacodynamic s are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area.

Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories.

In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis.

A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine.

Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination.

Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, ‘safe’ drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics.

In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless of the route of elimination of drug or metabolite.

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References

  1. 1.
    Desmet VJ. General pathology. In: Mclntyre N, Benhamou J-P, Bircher J, et al, editors. Oxford textbook of clinical hepatology. Oxford: Oxford University Press, 1991: 263–9Google Scholar
  2. 2.
    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991; 21: 42–69PubMedGoogle Scholar
  3. 3.
    Child CG. The liver and portal hypertension. Philadelphia: WB Saunders, 1964Google Scholar
  4. 4.
    Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophagus varices. Br J Surg 1973; 60: 646–9PubMedGoogle Scholar
  5. 5.
    St Peter JV, Awni WM. Quantifying hepatic function in the presence of liver disease with phenazone (Antipyrine) and its metabolites. Clin Pharmacokinet 1991; 20: 50–65PubMedGoogle Scholar
  6. 6.
    Brockmöller J, Roots I. Assessment of liver metabolic function. Clin Pharmacokinet 1994; 27: 216–48PubMedGoogle Scholar
  7. 7.
    Koren G, Beatty K, Seto A, et al. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 1992; 26: 363–71PubMedGoogle Scholar
  8. 8.
    Westphal J-F, Brogard J-M. Clinical pharmacokinetics of newer antibacterial agents in liver disease. Clin Pharmacokinet 1993; 24: 46–58PubMedGoogle Scholar
  9. 9.
    Branch RA, Shand DG. Propranolol disposition in chronic liver disease: a physiological approach. Clin Pharmacokinet 1976; 1: 264–79PubMedGoogle Scholar
  10. 10.
    Varin F, Huet P-M. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest 1985; 76: 1904–12PubMedGoogle Scholar
  11. 11.
    Reichen J, Egger B, Ohara N, et al. Determinants of hepatic function in liver cirrhosis in the rat. J Clin Invest 1988; 82: 2069–76PubMedGoogle Scholar
  12. 12.
    Reichen J. Hepatic spaces and transport in the perfused liver. In: Petzinger E, Kinne RK-J, Sies H, editors. Hepatic transport in organic substances. Berlin: Springer-Verlag, 1989: 45–56Google Scholar
  13. 13.
    Morgan DJ, McLean AJ. Therapeutic implications of impaired hepatic oxygen diffusion in chronic liver disease. Hepatology 1991; 14: 1280–2PubMedGoogle Scholar
  14. 14.
    Blaschke TF. Protein binding and kinetics of drugs in liver disease. Clin Pharmacokinet 1977; 2: 32–44PubMedGoogle Scholar
  15. 15.
    Tillement JP, Lhoste F, Giudiccelli JF. Disease and drug protein binding. Clin Pharmacokinet 1978; 3: 144–54PubMedGoogle Scholar
  16. 16.
    Perlik F, Janku I, Jedlicka J. Functional and non-functional liver blood flow in patients with liver cirrhosis measured by indocyanine green. Meth Find Exp Clin Pharmacol 1992; 14: 459–64Google Scholar
  17. 17.
    Callaghan R, Desmond PV, Pauli P, et al. Hepatic enzyme activity is the major factor determining elimination rate of highclearance drugs in cirrhosis. Hepatology 1993; 18: 54–60PubMedGoogle Scholar
  18. 18.
    Kraul H, Truckenbrodt J, Huster A, et al. Comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity. Eur J Clin Pharmacol 1991; 41: 475–80PubMedGoogle Scholar
  19. 19.
    Buters JTM, Zysset T, Reichen J. Metabolism of antipyrine in vivo in two rat models of liver cirrhosis. Biochem Pharmacol 1993; 46: 983–91PubMedGoogle Scholar
  20. 20.
    Murray M. P450 enzymes: inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23: 132–46PubMedGoogle Scholar
  21. 21.
    Guengerich FP, Turvy CG. Comparison of levels of several human microsomal cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J Pharm Exp Ther 1991; 256: 1189–94Google Scholar
  22. 22.
    Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450 IIIA in patients with severe liver disease. Clin Pharmacol Ther 1992; 51: 229–38PubMedGoogle Scholar
  23. 23.
    George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995; 21: 120–8PubMedGoogle Scholar
  24. 24.
    George J, Liddle C, Murray M, et al. Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. Biochem Pharmacol 1995; 49: 873–81PubMedGoogle Scholar
  25. 25.
    Blouin RA, Hamelin BA, Smith DA, et al. Fleroxacin pharmacokinetics in patients with liver cirrhosis. Antimicrob Agents Chemother 1992; 36: 632–8PubMedGoogle Scholar
  26. 26.
    Wensing G, Ohnhaus EE, Hoensch HP. Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease. Clin Pharmacol Ther 1990; 47: 698–705PubMedGoogle Scholar
  27. 27.
    May DG, Arns PA, Richards WO, et al. The disposition of dapsone in cirrhosis. Clin Pharmacol Ther 1992; 689–700Google Scholar
  28. 28.
    Kawasaki S, Imamura H, Bandai Y, et al. Direct evidence for the intact hepatocyte theory in patients with liver cirrhosis. Gastroenterology 1992; 102: 1351–5PubMedGoogle Scholar
  29. 29.
    Meyer B, Luo H, Bargetzi M, et al. Quantitation of intrinsic drug-metabolizing capacity in human liver biopsy specimens: support for the intact-hepatocyte theory. Hepatology 1991; 13: 475–81PubMedGoogle Scholar
  30. 30.
    Tanaka E, Ishikawa A, Yamamoto Y, et al. A simple useful method for the determination of hepatic function in patients with liver cirrhosis using caffeine and its three major dimethylmetabolites. Int J Clin Pharmacol Ther Toxicol 1992; 30: 336–41PubMedGoogle Scholar
  31. 31.
    Meyer-Wyss B, Renner E, Luo H, et al. Assessment of lidocaine metabolite formation in comparison with other quantitative liver function tests. J Hepatol 1993; 19: 133–9PubMedGoogle Scholar
  32. 32.
    Wensing G, Mönig H, Ohnhaus EE, et al. Pharmacokinetics of encainide in patients with cirrhosis. Cardiovasc Drugs Ther 1991; 5: 733–40PubMedGoogle Scholar
  33. 33.
    Razak TA, McNeil JJ, Sewell RB, et al. The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine. Clin Pharmacol Ther 1990; 47: 463–9PubMedGoogle Scholar
  34. 34.
    Sotaniemi EA, Rautio A, Bäckstrom M, et al. CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients. Br J Clin Pharmacol 1995; 39: 71–6PubMedGoogle Scholar
  35. 35.
    Horsmans Y, Desager J-P, Daenens C, et al. D-propoxyphene and norpropoxyphene kinetics after the oral administration of D-propoxyphene: a new approach to liver function? J Hepatol 1994; 21: 283–91PubMedGoogle Scholar
  36. 36.
    Schenker S, Bergstrom RF, Wolen RL, et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44: 353–9PubMedGoogle Scholar
  37. 37.
    Kawasaki S, Sugiyama Y, Iga T, et al. Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases. Clin Pharmacol Ther 1988; 44: 217–24PubMedGoogle Scholar
  38. 38.
    Colli A, Buccino G, Cocciolo M, et al. Disposition of a flowlimited drug (lidocaine) and a metabolic capacity-limited drug (theophylline) in liver cirrhosis. Clin Pharmacol Ther 1988; 44: 642–9PubMedGoogle Scholar
  39. 39.
    Morgan DJ, Smallwood RA. Hepatic drug clearance in chronic liver disease: can we expect to find a universal, quantitative marker of hepatic function? Hepatology 1989; 10: 893–5PubMedGoogle Scholar
  40. 40.
    Martinez-Hernandez A, Martinez J. The role of capilliarization in hepatic failure: studies in carbon tetrachloride-induced cirrhosis. Hepatology 1991; 14: 864–74PubMedGoogle Scholar
  41. 41.
    Fenyves D, Gariépy L, Villeneuve J-P. Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat. Hepatology 1993; 301–6Google Scholar
  42. 42.
    Gariépy L, Fenyves D, Kassissia I, et al. Clearance by the liver in cirrhosis: II. Characterization of propranolol uptake with the multiple-indicator dilution technique. Hepatology 1993; 823–31Google Scholar
  43. 43.
    Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology 1991; 13: 786–95PubMedGoogle Scholar
  44. 44.
    Hickey PL, Angus PW, McLean AJ, et al. Oxygen supplementation restores theophylline clearance to normal in cirrhotic rats. Gastroenterology 1995; 108: 1504–9PubMedGoogle Scholar
  45. 45.
    Watanabe Y, Püschel GP, Gardemann A, et al. Presinusoidal and proximal intrasinusoidal confluence of hepatic artery and portal vein in rat liver: functional evidence by orthograde and retrograde bivascular perfusion. Hepatology 1994; 19: 1198–207PubMedGoogle Scholar
  46. 46.
    Pang KS, Sherman IA, Schwab AJ, et al. Role of the hepatic artery in the metabolism of phenacetin and acetaminophen: an intravital microscopic and multiple-indicator dilution study in perfused rat liver. Hepatology 1994; 20: 672–83PubMedGoogle Scholar
  47. 47.
    Kassissia I, Brault A, Huet P-M. Hepatic artery and portal vein vascularization of normal and cirrhotic rat liver. Hepatology 1994; 19: 1189–97PubMedGoogle Scholar
  48. 48.
    Heinzow B, Corbett H, Constantinides S, et al. Interaction between oral hydralazine and propranolol. I: Changes in absorption, presystemic clearance and splanchnic blood flow. J Pharm Exp Ther 1984; 229: 509–14Google Scholar
  49. 49.
    Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev 1971; 51: 23–65PubMedGoogle Scholar
  50. 50.
    Reichen J, Hirlinger A, Ha HR, et al. Chronic verapamil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis. J Hepatol 1986; 3: 49–58PubMedGoogle Scholar
  51. 51.
    Reichen J, Le M. Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. J Clin Invest 1986; 78: 448–55PubMedGoogle Scholar
  52. 52.
    Lay C-S, Tsai Y-T, Kong C-W, et al. The influence of verapamil and nifedipine on hepatic indocyanine green clearance in patients with HBsAg-positive cirrhosis and ascites. Clin Pharmacol Ther 1988; 44: 453–7PubMedGoogle Scholar
  53. 53.
    Merkel C, Bolognesi M, Angeli P, et al. Lack of effect of verapamil and isosorbide dinitrate on the hepatic clearance of indocyanine green in cirrhosis. Br J Clin Pharmacol 1990; 30: 221–7PubMedGoogle Scholar
  54. 54.
    Albillos A, Ba―ares R, Barrios C, et al. Oral administration of clonidine in patients with alcoholic cirrhosis. Gastroenterology 1992; 102: 248–54PubMedGoogle Scholar
  55. 55.
    Iwao T, Toyonaga A, Ikegami M, et al. Nicardipine infusion improved hepatic function but failed to reduce hepatic venous pressure gradient in patients with cirrhosis. Am J Gastroenterol 1992; 87: 326–31PubMedGoogle Scholar
  56. 56.
    García-Pagán JC, Feu F, Luca A, et al. Nicardipine increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis. J Hepatol 1994; 20: 792–6PubMedGoogle Scholar
  57. 57.
    Jones DB, Mihaly GW, Smallwood RA, et al. Differential effects of hypoxia on the disposition of propranolol and sodium taurocholate by the isolated perfused rat liver. Hepatology 1984; 4: 461–6PubMedGoogle Scholar
  58. 58.
    Taburet A-M, Naveau S, Zorza G, et al. Pharmacokinetics of zidovudine in patients with liver cirrhosis. Clin Pharmacol Ther 1990; 47: 731–9PubMedGoogle Scholar
  59. 59.
    Magnard O, Louchahi K, Tod M, et al. Pharmacokinetics of diacerein in patients with liver cirrhosis. Biopharm Drug Dispos 1993; 14: 401–8PubMedGoogle Scholar
  60. 60.
    Macdonald JI, Wallace SM, Mahachai V, et al. Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis. Eur J Clin Pharmacol 1992; 42: 471–4PubMedGoogle Scholar
  61. 61.
    Debinski HS, Lee CS, Danks JA, et al. Localization of 5′-diphosphate-glucuronosyltransferase in human liver injury. Gastroenterology 1995; 108: 1464–9PubMedGoogle Scholar
  62. 62.
    Magueur E, Hagege H, Attali P, et al. Pharmacokinetics of metoclopramide in patients with liver cirrhosis. Br J Clin Pharmacol 1991; 31: 185–7PubMedGoogle Scholar
  63. 63.
    Albani F, Tamè MR, DePalma R, et al. Kinetics of intravenous metoclopramide in patients with hepatic cirrhosis. Eur J Clin Pharmacol 1991; 40: 423–5PubMedGoogle Scholar
  64. 64.
    Acocella G, Bonool L, Garimoldi M, et al. Kinetics of rifampin and isoniazid administered alone and in combination to normal subjects and patients with liver disease. Gut 1972; 13: 47–53PubMedGoogle Scholar
  65. 65.
    Levi AJ, Sherlock S, Walker D. Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous drug therapy. Lancet 1968; 1: 1275–9PubMedGoogle Scholar
  66. 66.
    Huet P-M, Goresky CA, Villeneuve JP, et al. Assessment of liver microcirculation in human cirrhosis. J Clin Invest 1982; 70: 1234–44PubMedGoogle Scholar
  67. 67.
    Nambu M, Iijima T. Indocyanine green (ICG) test before and after exercise in patients with chronic liver disease. Gastroenterol Jpn 1990; 25: 212–7PubMedGoogle Scholar
  68. 68.
    Krähenbühl S, Grass P, Surve A, et al. Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease. Eur J Clin Pharmacol 1993; 45: 247–53PubMedGoogle Scholar
  69. 69.
    Demotes-Mainard F, Vincon G, Amouretti M, et al. Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis. Clin Pharmacol Ther 1991; 49: 263–9PubMedGoogle Scholar
  70. 70.
    Demotes-Mainard F, Vinçon G, Labt L, et al. Cefpiramide kinetics and plasma protein binding in cholestasis. Br J Clin Pharmacol 1994; 37: 295–7Google Scholar
  71. 71.
    Hu OY-P, Tang H-S, Chang C-L. The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone — a novel galactose single-point method as a measure of residual liver function. Biopharm Drug Dispos 1994; 15: 563–76PubMedGoogle Scholar
  72. 72.
    Furuta S, Kiyosawa K, Higuchi M, et al. Pharmacokinetics of temocapril, an ACE inhibitor with preferential biliary excretion, in patients with impaired liver function. Eur J Clin Pharmacol 1993; 44: 383–5PubMedGoogle Scholar
  73. 73.
    Magorian T, Wood P, Caldwell J, et al. The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients with liver disease. Anesth Analg 1995; 80: 754–9PubMedGoogle Scholar
  74. 74.
    Luppino MA, McLean AJ. Plasma and tissue distribution of bismuth in normal and cirrhotic rats. Analyst 1995; 120: 883–6PubMedGoogle Scholar
  75. 75.
    von Moltke LL, Abernethy DR, Kaplan MM, et al. Antipyrine kinetics in patients with primary biliary cirrhosis. J Clin Pharmacol 1993; 33: 75–7Google Scholar
  76. 76.
    Ohnishi A, Tsuboi Y, Ishizaki T, et al. Kinetics and dynamics of enalapril in patients with liver cirrhosis. Clin Pharmacol Ther 1989; 45: 657–65PubMedGoogle Scholar
  77. 77.
    Baba T, Murabayashi S, Tomiyama T, et al. The pharmacokinetics of enalapril in patients with compensated liver cirrhosis. Br J Clin Pharmacol 1990; 29: 766–9PubMedGoogle Scholar
  78. 78.
    Gross V, Treher E, Haag K, et al. Angiotensin-converting enzyme (ACE)-inhibition in cirrhosis: pharmacokinetics and dynamics of the ACE-inhibitor cilazapril (Ro 31-2848)1. J Hepatol 1993; 17: 40–7PubMedGoogle Scholar
  79. 79.
    Thiollet M, Funck-Brentano C, Grange J-D, et al. The pharmacokinetics of perindopril in patients with liver cirrhosis. Br J Clin Pharmac 1992; 33: 326–8Google Scholar
  80. 80.
    Ludwig EA, Kong A-N, Camara DS, et al. Pharmacokinetics of methylprednisolone hemisuccinate and methylpredinisolone in chronic liver disease. J Clin Pharmacol 1993; 33: 805–10PubMedGoogle Scholar
  81. 81.
    Kawai S, Ichikawa Y, Homma M. Differences in metabolic properties among cortisol, prednisolone and dexamethasone in liver and renal disease: accelerated metabolism of dexamethasone in renal failure. J Clin Endocrinol Metab 1985; 60: 848–54PubMedGoogle Scholar
  82. 82.
    Renner E, Horber FF, Jost G, et al. Effect of liver function on the metabolism of prednisone and prednisolone in humans. Gastroenterology 1986; 90: 819–28PubMedGoogle Scholar
  83. 83.
    Tucker GT, Lennard MS. Enantiomer specific pharmacokinetics. Pharmacol Ther 1990; 45: 309–29PubMedGoogle Scholar
  84. 84.
    Neugebauer G, Gabor M, Reiff K. Disposition of carvedilol enantiomers in patients with liver cirrhosis: evidence for disappearance of stereoselective first-pass extraction. J Cardiovasc Pharmacol 1992; 19 Suppl.: S142–6PubMedGoogle Scholar
  85. 85.
    Caldwell J, Hutt AJ, Fournel-Gigleux S. The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences. Biochem Pharmacol 1988; 37: 105–14PubMedGoogle Scholar
  86. 86.
    Juhl RP, van Thiel DH, Dittert LW, et al. Ibuprofen and sulindac kinetics in alcoholic liver disease. Clin Pharmacol Ther 1983; 34: 104–9PubMedGoogle Scholar
  87. 87.
    Li G, Treiber G, Maier K, et al. Disposition of ibuprofen in patients with liver cirrhosis. Clin Pharmacokinet 1993; 25: 154–63PubMedGoogle Scholar
  88. 88.
    Cook DR, Freeman JA, Lai AA, et al. Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure. Br J Anaesth 1992; 69: 580–5PubMedGoogle Scholar
  89. 89.
    Head-Rapson AG, Devlin JC, Parker CJR, et al. Pharmacokinetics of the three isomers of mivacurium and pharmacodynamics of the chiral mixture in hepatic cirrhosis. Br J Anaesth 1994; 73: 613–8PubMedGoogle Scholar
  90. 90.
    Papadakis MA, Arieff AI. Progressive deterioration of renal function in non-azotemic cirrhotic patients with ascites: a prospective study. Kidney Int 1985; 27: 149Google Scholar
  91. 91.
    Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in cirrhosis. Am J Med 1987; 82: 945–52PubMedGoogle Scholar
  92. 92.
    Caregaro L, Menon F, Angeli P, et al. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 1994; 154: 201–5PubMedGoogle Scholar
  93. 93.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41PubMedGoogle Scholar
  94. 94.
    Granneman GR, Mahr G, Locke C, et al. Pharmacokinetics of temafloxacin in patients with liver impairment. Clin Pharmacokinet 1992; 22: 24–32PubMedGoogle Scholar
  95. 95.
    Mazzei T, Surrenti C, Novelli A, et al. Pharmacokinetics of azithromycin in patients with impaired hepatic function. J Antimicrob Chemother 1993; 31: 57–63PubMedGoogle Scholar
  96. 96.
    El Touny M, El Guinaidy A, Abdel Barry A, et al. Pharmacokinetics of ceftazidime in patients with liver cirrhosis and ascites. J Antimicrob Chemother 1991; 28: 95–100PubMedGoogle Scholar
  97. 97.
    Vinçon G, Baldit C, Couzigou P, et al. Pharmacokinetics of famotidine in patients with cirrhosis and ascites. Eur J Clin Pharmacol 1992; 43: 559–62PubMedGoogle Scholar
  98. 98.
    Morgan MY, Stambuk D, Cottrell J, et al. Pharmacokinetics of famotidine in normal subjects and in patients with chronic liver disease. Aliment Pharmacol Ther 1990; 4: 83–96PubMedGoogle Scholar
  99. 99.
    D’Honneur G, Khalil M, Dominique C. Pharmacokinetics and pharmacodynamics of pipecuronium in patients with cirrhosis. Anesth Analg 1993; 77: 1203–6PubMedGoogle Scholar
  100. 100.
    Simons FER, Watson WTA, Minuk GY, et al. Cetirizine pharmacokinetics and pharmacodynamics in primary biliary cirrhosis. J Clin Pharmacol 1993; 33: 949–54PubMedGoogle Scholar
  101. 101.
    Ruhnke M, Yeates RA, Pfaff G, et al. Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis. J Antimicrob Chemother 1995; 35: 641–7PubMedGoogle Scholar
  102. 102.
    Diez J, Simon MA, Anton F, et al. Tubular sodium handling in cirrhotic patients with ascites as analysed by the renal lithium clearance method. Eur J Clin Invest 1990; 20: 266–71PubMedGoogle Scholar
  103. 103.
    Angeli P, Gatta A, Caregaro L, et al. Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance. Eur J Clin Invest 1990; 20: 111–7PubMedGoogle Scholar
  104. 104.
    Orlando R, Sawadogo A, Miglioli PA, et al. Oral disposition kinetics of ofloxacin in patients with compensated liver cirrhosis. Chemotherapy 1992; 38: 1–6PubMedGoogle Scholar
  105. 105.
    Silvain C, Bouquet S, Breux JP, et al. Oral pharmacokinetics and ascitic fluid penetration of ofloxacin in cirrhosis. Eur J Clin Pharmacol 1989; 37: 261–5PubMedGoogle Scholar
  106. 106.
    Ohnishi K. Pharmacokinetics of famotidine after intravenous administration in liver disease. Am J Gastroenterol 1991; 86: 41–5PubMedGoogle Scholar
  107. 107.
    Lebrec D, Gaudin C, Benhamou J-P. Pharmacokinetics of lometloxacin in patients with cirrhosis. Am J Med 1992; 92 Suppl.: 41S–44SPubMedGoogle Scholar
  108. 108.
    Triger DR, Granai F, Woodcock J, et al. Multiple-dose pharmacokinetics of rufloxacin in patients with cirrhosis. Hepatology 1993; 18: 847–52PubMedGoogle Scholar
  109. 109.
    Solis-Herruzo JA, Gonzalez-Gamarra A, Castellano G, et al. Metabolic clearance rate of arginine vasopressin in patients with cirrhosis. Hepatology 1992; 16: 974–9PubMedGoogle Scholar
  110. 110.
    Sungaila I, Bartle WR, Walker SE, et al. Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites. Gastroenterology 1992; 102: 1680–5PubMedGoogle Scholar
  111. 111.
    Danziger LH, Martin SJ, Blum RA. Central nervous system toxicity associated with meperidine use in hepatic disease. Pharmacotherapy 1994; 14: 235–8PubMedGoogle Scholar
  112. 112.
    El Touny M, El Guinaidy M, Abdel Barry M, et al. Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites. J Antimicrob Chemother 1992; 30: 387–95PubMedGoogle Scholar
  113. 113.
    Schwartz S, Brater DC, Pound D, et al. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide in patients with cirrhosis. Clin Pharmacol Ther 1993; 54: 90–7PubMedGoogle Scholar
  114. 114.
    Sherlock S. Hepatic cirrhosis. In: Diseases of the liver and biliary system, 8th ed. Oxford: Blackwell Scientific, 1989: 410–24Google Scholar
  115. 115.
    Khodadoost J, Glass JBG. Erosive gastritis and acute gastroduodenal ulcerations as sources of upper gastrointestional bleeding in liver cirrhosis. Digestion 1972; 7: 129–38PubMedGoogle Scholar
  116. 116.
    Chesta J, Lillo R, Defilippi C, et al. Orocecal transit time and gastric emptying in patients with cirrhosis [abstract]. Gastroenterology 1991; 100: A43Google Scholar
  117. 117.
    Wegener M, Schaffstein J, Dikger U, et al. Gastrointestinal transit of solid-liquid meal in chronic alcoholics. Digest Dis Sci 1991; 36: 917–23PubMedGoogle Scholar
  118. 118.
    Isobe H, Sakai H, Satoh M, et al. Delayed gastric emptying in patients with liver cirrhosis. Digest Dis Sci 1994; 39: 983–7PubMedGoogle Scholar
  119. 119.
    Fredrick MJ, Pound DC, Hall SD, et al. Furosemide absorption in patients with cirrhosis. Clin Pharmacol Ther 1991; 49: 241–7PubMedGoogle Scholar
  120. 120.
    Amodio P, Lauro S, Rondana M, et al. Theophylline pharmacokinetics and liver function indexes in chronic liver disease. Respiration 1991; 58: 106–11PubMedGoogle Scholar
  121. 121.
    Bauer LA, O’Sullivan T, Reiss WG, et al. Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis. Br J Clin Pharmacol 1994; 37: 375–81PubMedGoogle Scholar
  122. 122.
    Taburet AM, Attali P, Bourget P, et al. Pharmacokinetics of ornidazole in patients with acute viral hepatitis, alcoholic cirrhosis, and extrahepatic cholestasis. Clin Pharmacol Ther 1989; 45: 373–9PubMedGoogle Scholar
  123. 123.
    Ali HA, El-Yazigi A, Sieck JO, et al. Antipyrine clearance and metabolite excretion in patients with chronic hepatitis C. J Hepatol 1995; 22: 17–21PubMedGoogle Scholar
  124. 124.
    Villeneuve JP, Thibeault MJ, Ampelas M, et al. Drug disposition in patients with HBsAg-positive chronic liver disease. Digest Dis Sci 1987; 32: 710–4PubMedGoogle Scholar
  125. 125.
    Sotaniemi EA, Pelkonen RO, Mokka RE, et al. Impairment of drug metabolism in patients with liver cancer. Eur J Clin Invest 1977; 7: 269–74PubMedGoogle Scholar
  126. 126.
    Homeida M, Roberts CJC, Halliwell M, et al. Antipyrine clearance per unit volume liver: an assessment of hepatic function in chronic liver disease. Gut 1979; 20: 596–601PubMedGoogle Scholar
  127. 127.
    Virgolini I, Muller C, Klepetko W, et al. Decreased hepatic function in patients with hepatoma or liver metastasis monitored by a hepatocyte specific galactosylated radioligand. Br J Cancer 1990; 61; 937–41PubMedGoogle Scholar
  128. 128.
    Robertz-Vaupel GM, Lindecken KD, Edeki T, et al. Disposition of antipyrine in patients with extensive metastatic liver disease. Eur J Clin Pharmacol 1992; 42: 465–9PubMedGoogle Scholar
  129. 129.
    Preiss R, Matthias M, Sohr R, et al. Pharmacokinetics of adriamycin, adriamycinol, and antipyrine in patients with moderate tumor involvement of the liver. J Cancer Res Clin Oncol 1987; 113: 593–8PubMedGoogle Scholar
  130. 130.
    Noda S, Kawata S, Miyoshi S, et al. Antipyrine clearance per unit liver volume in cirrhotics with and without hepatocellular carcinoma indicating a correlation with histological change of the liver. Gastroenterol Jpn 1989; 24: 159–63PubMedGoogle Scholar
  131. 131.
    Dobbs NA, Twelves C, Rizzi P, et al. Epirubicin in hepatocellular carcinoma: pharmacokinetics and clinical activity. Cancer Chemother Pharmacol 1994; 34: 405–10PubMedGoogle Scholar
  132. 132.
    Homeida MMA, Ali BMO, Arbab BMO, et al. Propranolol disposition in patients with hepatosplenic schistosomiasis. Br J Clin Pharmacol 1987; 24: 393–6PubMedGoogle Scholar
  133. 133.
    Cukier A, Strauss E, Filho MT, et al. Theophylline metabolism in patients with hepatosplenic mansoniasis and cirrhosis. J Hepatol 1992; 15: 35–9PubMedGoogle Scholar
  134. 134.
    Daneshmend TK, Homeida M, Kaye CM, et al. Disposition of oral metronidazole in hepatic cirrhosis and in hepatosplenic schistosomiasis. Gut 1982; 23: 807–13PubMedGoogle Scholar
  135. 135.
    Daneshmend TK, Homeida MA. Oxamniquine pharmacokinetics in hepatosplenic schistosomiasis in the Sudan. J Antimicrob Chemother 1987; 19: 87–93PubMedGoogle Scholar
  136. 136.
    Kroboth PD, Maxwell RA, Fleishaker JC, et al. Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects. J Clin Pharmacol 1991; 31: 580–6PubMedGoogle Scholar
  137. 137.
    Robin DW, Lee MH, Hasan SS, et al. Triazolam in cirrhosis: pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993; 43: 630–7Google Scholar
  138. 138.
    Devlin JC, Head-Rapson AG, Parker CJR, et al. Pharmacodynamics of mivacurium chloride in patients with hepatic cirrhosis. Br J Anaesth 1993; 71: 227–31PubMedGoogle Scholar
  139. 139.
    Levy G. Effect of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of mivacurium in humans. Pharm Res 1994; 11: 772–3PubMedGoogle Scholar
  140. 140.
    Khalil M, D’Honneur G, Duvaldestin P, et al. Pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. Anesthesiology 1994; 80: 1241–7PubMedGoogle Scholar
  141. 141.
    Janku I, Perlik F, Tkaczykova M, et al. Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects. Eur J Clin Pharmacol 1992; 42: 337–40PubMedGoogle Scholar
  142. 142.
    Sherlock S. Diseases of the liver and biliary system. Oxford: Blackwell, 1985: 39–42Google Scholar
  143. 143.
    Duvaldestin P, Chauvin M, Lebrault C, et al. Effect of upper abdominal surgery and cirrhosis upon the pharmacokinetics of methohexital. Acta Anaesthesiol Scand 1991; 35: 159–63PubMedGoogle Scholar
  144. 144.
    Drouet-Coassolo C, Iliadis A, Coassolo P, et al. Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers. Fundam Clin Pharmacol 1990; 4: 643–51PubMedGoogle Scholar
  145. 145.
    El Touny M, El Guinaidy M, Abdel Bary M, et al. Pharmacokinetics of cefodizime in patients with liver cirrhosis and ascites. Chemotherapy 1992; 38: 201–5PubMedGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Denis J. Morgan
    • 1
  • Allan J. McLean
    • 2
  1. 1.Department of Pharmaceutics, Victorian College of PharmacyMonash UniversityMelbourneAustralia
  2. 2.Alfred Hospital Department of Clinical Pharmacology and Monash University Department of Medicine, Alfred Healthcare GroupMelbourneAustralia

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