Clinical Pharmacokinetics

, Volume 37, Issue 5, pp 399–431 | Cite as

Effects of Liver Disease on Pharmacokinetics

An Update
  • Vanni Rodighiero
Review Articles Special Populations

Abstract

Liver disease can modify the kinetics of drugs biotransformed by the liver. This review updates recent developments in this field, with particular emphasis on cytochrome P450 (CYP). CYP is a rapidly expanding area in clinical pharmacology. The information currently available on specific isoforms involved in drug metabolism has increased tremendously over the latest years, but knowledge remains incomplete.

Studies on the effects of liver disease on specific isoenzymes of CYP have shown that some isoforms are more susceptible than others to liver disease. A detailed knowledge of the particular isoenzyme involved in the metabolism of a drug and the impact of liver disease on that enzyme can provide a rational basis for dosage adjustment in patients with hepatic impairment.

The capacity of the liver to metabolise drugs depends on hepatic blood flow and liver enzyme activity, both of which can be affected by liver disease. In addition, liver failure can influence the binding of a drug to plasma proteins. These changes can occur alone or in combination; when they coexist their effect on drug kinetics is synergistic, not simply additive. The kinetics of drugs with a low hepatic extraction are sensitive to hepatic failure rather than to liver blood flow changes, but drugs having a significant first-pass effect are sensitive to alterations in hepatic blood flow.

The drugs examined in this review are: cardiovascular agents (angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, calcium antagonists, ketanserin, antiarrhythmics and hypolipidaemics), diuretics (torasemide), psychoactive and anticonvulsant agents (benzodiazepines, flumazenil, antidepressants and tiagabine), antiemetics (metoclopramide and serotonin antagonists), antiulcers (acid pump inhibitors), anti-infectives and antiretroviral agents (grepafloxacin, ornidazole, pefloxacin, stavudine and zidovudine), immunosuppressants (cyclosporin and tacrolimus), naltrexone, tolcapone and toremifene.

According to the available data, the kinetics of many drugs are altered by liver disease to an extent that requires dosage adjustment; the problem is to quantify the required changes. Obviously, this requires the evaluation of the degree of hepatic impairment. At present there is no satisfactory test that gives a quantitative measure of liver function and its impairment. A critical evaluation of these methods is provided. Guidelines providing a rational basis for dosage adjustment are illustrated.

Finally, it is important to consider that liver disease not only affects pharmacokinetics but also pharmacodynamics. This review also examines drugs with altered pharmacodynamics.

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References

  1. 1.
    Rodighiero V. Effects of liver disease on pharmacokinetics. Ital J Gastroenterol 1987; 19: 149–58.Google Scholar
  2. 2.
    Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clin Pharmacokinet 1988; 15: 396–420.PubMedCrossRefGoogle Scholar
  3. 3.
    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991; 21: 42–69.PubMedCrossRefGoogle Scholar
  4. 4.
    Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet 1995; 29 (5): 370–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Paintaud G, Bechtel Y, Brientini MP, et al. Effects of liver diseases on drug metabolism. Therapie 1996; 51 (4): 384–9.PubMedGoogle Scholar
  6. 6.
    Shargel L, Yu AB. Applied biopharmaceutics and pharmacokinetics. Stamford (CT): Appleton and Lange, 1999: 353–98.Google Scholar
  7. 7.
    Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32 (3): 210–58.PubMedCrossRefGoogle Scholar
  8. 8.
    Murray M. P450 enzymes: inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23 (2): 132–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Gu L, Gonzalez FJ, Kalow W, et al. Biotransfonnation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 1992; 2 (2): 73–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Holstege A, Staiger M, Haag K, et al. Correlation of caffeine elimination and Child’s classification in liver cirrhosis. Klin Wochenschr 1989; 4 67 (1): 6–15.CrossRefGoogle Scholar
  11. 11.
    Child CG. The liver and portal hypertension. Philadelphia (PA): WB Saunders, 1964.Google Scholar
  12. 12.
    Pugh RN, Murray Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60 (8): 646–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Scott NR, Stambuk D, Chakraborty J, et al. The pharmacokinetics of caffeine and its dimethylxanthine metabolites in patients with chronic liver disease. Br J Clin Pharmacol 1989; 27 (2): 205–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis FW, Rector Jr WG. Caffeine clearance in cirrhosis: the value of simplified determinations of liver metabolic capacity. J Hepatol 1992; 14 (2–3): 157–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Braillon A, Cales P, Valla D, et al. Influence of the degree of liver failure on systemic and splanchnic haemodynamics and on response to propranolol in patients with cirrhosis. Gut 1986; 27 (10): 1204–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Pelkonen O, Raunio H, Rautio A, et al. Coumarin 7-hydroxylase: characteristics and regulation in mouse and man. J Ir Coll Phys Surg 1993; 22 Suppl. 1: 24–8.Google Scholar
  17. 17.
    Sotaniemi EA, Rautio A, Backstrom 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 (1): 71–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Kraul H, Truckenbrodt J, Huster A, et al. A comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity. Eur J Clin Pharmacol 1991; 41 (5): 475–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Gillis JC, Markham A. Irbesartan: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension. Drugs 1997; 54 (6): 885–902.PubMedCrossRefGoogle Scholar
  20. 20.
    Relling MV, Aoyama T, Gonzalez FJ, et al. Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. J Pharmacol Exp Ther 1990; 252 (1): 442–7.PubMedGoogle Scholar
  21. 21.
    Adedoyin A, Arns PA, Richards WO, et al. Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 1998; 64 (1): 8–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Marino MR, Langenbacher KM, Raymond RH, et al. Pharmacokinetics and pharmacodynamics of irbesartan in patients with hepatic cirrhosis. J Clin Pharmacol 1998; 38 (4): 347–56.PubMedGoogle Scholar
  23. 23.
    Howden CW, Birnie GG, Brodie MJ. Drug metabolism in liver disease. Pharmacol Ther 1989; 40 (3): 439–74.PubMedCrossRefGoogle Scholar
  24. 24.
    Arns PA, Adedoyin A, DiBisceglie AM, et al. Mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis. Clin Pharmacol Ther 1997; 62 (5): 527–37.PubMedCrossRefGoogle Scholar
  25. 25.
    Frye RF, Matzke GR, Adedoyin A, et al. Validation of the five-drug ‘Pittsburgh cocktail’ approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther 1997; 62 (4): 365–76.PubMedCrossRefGoogle Scholar
  26. 26.
    Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24 (5): 475–90.PubMedGoogle Scholar
  27. 27.
    Huang YS, Lee SD, Deng JF, et al. Measuring lidocaine metabolite monoethylglycinexylidide as a quantitative index of hepatic function in adults with chronic hepatitis and cirrhosis. J Hepatol 1993; 19 (1): 140–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Shiffman ML, Luketic VA, Sanyal AJ, et al. Hepatic lidocaine metabolism and liver histology in patients with chronic hepatitis and cirrhosis. Hepatology 1994; 19 (4): 933–40.PubMedCrossRefGoogle Scholar
  29. 29.
    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 (1): 120–8.PubMedGoogle Scholar
  30. 30.
    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; 30; 49 (7): 873–81.PubMedCrossRefGoogle Scholar
  31. 31.
    Burnier M, Biollaz J. Pharmacokinetic optimisation of angiotensin converting enzyme (ACE) inhibitor therapy. Clin Pharmacokinet 1992; 22: 375–84.PubMedCrossRefGoogle Scholar
  32. 32.
    Horvath AM, Olson SC, Ferry JJ, et al. Pharmacokinetics of quinalapril and its active metabolite, quinalaprilat, in patients with hepatic impairment. J Clin Pharmacol 1988; 28: 917.Google Scholar
  33. 33.
    Gross V, Schölmerich J, Treher E, et al. Altered kinetics of cilazapril (Ro 31-2848) and cilazaprilat (Ro 31-3113) in patients with liver cirrhosis. Hepatology 1988; 8: 1382.Google Scholar
  34. 34.
    Hayes PC, Plevis JN, Bouchier IAD. Pharmacokinetics of enalapril and lisinopril in subjects with normal and impaired hepatic function. J Hum Hypertens 1989; 3: 153–8.PubMedGoogle Scholar
  35. 35.
    Ohnishi A, Tsuboi Y, Ishizaki T. Kinetics and dynamics of enalapril in patients with liver cirrhosis. Clin Pharmacol Ther 1989; 45: 657–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Lo MW, Golberg MR, McCrea JB, et al. Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Ther 1995; 58: 641–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Goa KL, Wagstaff AJ. Losartan potassium. A review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996; 51: 820–45.PubMedCrossRefGoogle Scholar
  38. 38.
    Flesch G, Lloyd MP. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 1997; 52: 115–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Brookman LJ, Rolan PE, Benjamin IS, et al. Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther 1997; 62: 272–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Kelly JC, O’Malley K. Clinical pharmacokinetics of calcium antagonists: an update. Clin Pharmacokinet 1992; 22: 416–33.PubMedCrossRefGoogle Scholar
  41. 41.
    Regärdh CG, Edgar B, Olsson R, et al. Pharmacokinetics of felodipine in patients with liver disease. Eur J Clin Pharmacol 1989; 36: 473–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang SX, Sutfin T, Baarnhielm C, et al. Contribution of the intestine to the first pass metabolism of felodipine in the rat. J Pharmacol Exp Ther 1989; 250: 632–6.PubMedGoogle Scholar
  43. 43.
    Brodgen RN, Benfield P. Gallopamil: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in ischaemic heart disease. Drugs 1994; 47: 93–115.CrossRefGoogle Scholar
  44. 44.
    Kaim AAH, Farker K. Pharmacokinetics and pharmacodynamics of gallopamil in patients with liver cirrhosis [abstract 36]. Naunyn Schmiedebergs Arch Pharmacol 1992; 345 Suppl. R9.Google Scholar
  45. 45.
    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: 463–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Kleinbloesem CH, van Harten J, Wilson JPH, et al. Nifedipine: kinetic and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration. Clin Pharmacol Ther 1986; 40: 21–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Ene MD, Roberts CJC. Pharmacokinetics of nifedipine after oral administration in chronic liver disease. J Clin Pharmacol 1987; 27: 1001–4.PubMedGoogle Scholar
  48. 48.
    Gengo FM, Fagan SC, Krol G, et al. Nimodipine disposition and haemodynamic effects in patients with cirrhosis and age-matched controls. Br J Clin Pharmacol 1987; 23: 47–53.PubMedCrossRefGoogle Scholar
  49. 49.
    van Harten J, van Brummelen P, Wilson JHP, et al. Nisoldipine: kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration. Eur J Clin Pharmacol 1988; 34: 387–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Davidsson GK, Edwards JS, Davidson C. The effect of age and liver disease on the pharmacokinetics of the calcium antagonist, nisoldipine. Curr Med Res Opin 1995; 13: 285–97.PubMedCrossRefGoogle Scholar
  51. 51.
    Dylevicz P, Kirch W, Santos SR, et al. Bioavailability and elimination of nitrendipine in liver disease. Eur J Clin Pharmacol 1987; 32: 563–8.CrossRefGoogle Scholar
  52. 52.
    Lasseter KC, Shamblen EC, Murdoch AA, et al. Steady-state pharmacokinetics of nitrendipine in hepatic insufficiency. J Cardiovasc Pharmacol 1984; 6 Suppl. 7: S977–81.PubMedGoogle Scholar
  53. 53.
    Persson B, Heykants J, Hedner T. Clinical pharmacokinetics of ketanserin. Clin Pharmacokinet 1991; 20: 263–79.PubMedCrossRefGoogle Scholar
  54. 54.
    Lebrec D, Hadengue A, Gaudin C, et al. Pharmacokinetics of ketanserin in patients with cirrhosis. Clin Pharmacokinet 1990; 19: 160–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Nestico PF, Morganroth J, Horowitz LN. New antiarrhythmic drugs. Drugs 1988; 35 (3): 286–319.PubMedCrossRefGoogle Scholar
  56. 56.
    McQuinn RL, Pentikäinen PJ, Chang SF, et al. Pharmacokinetics of flecainide in patients with cirrhosis of the liver. Clin Pharmacol Ther 1988; 44: 566–72.PubMedCrossRefGoogle Scholar
  57. 57.
    Forland SC, Burgess E, Blair AD, et al. Oral flecainide pharmacokinetics in patients with impaired renal function. J Clin Pharmacol 1988; 28 (3): 259–67.PubMedGoogle Scholar
  58. 58.
    Monk JP, Brogden RN. Mexiletine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 1990; 40: 374–411.PubMedCrossRefGoogle Scholar
  59. 59.
    Pentikäinen PJ, Hietakorpi S, Halinen MO, et al. Cirrhosis of the liver markedly impairs the elimination of mexiletine. Eur J Clin Pharmacol 1986; 30: 83–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Bryson HM, Palmer KJ, Langtry HD, et al. Propafenone: a reappraisal of its pharmacology, pharmacokinetics and therapeutic use in cardiac arrhythmias. Drugs 1993; 45: 85–130.PubMedCrossRefGoogle Scholar
  61. 61.
    Lee JT, Yee YG, Dorian P, et al. Influence of hepatic dysfunction on the pharmacokinetics of propafenone. J Clin Pharmacol 1987; 27; 384–9.PubMedGoogle Scholar
  62. 62.
    Plosker GL, Wagstaff A. Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia. Drugs 1996; 51: 433–59.PubMedCrossRefGoogle Scholar
  63. 63.
    Deslypere JP. Clinical implications of biopharmaceutical properties of fluvastatin. Am J Cardiol 1994; 73: 12–7D.CrossRefGoogle Scholar
  64. 64.
    Haria M, McTavish D. Pravastatin: a reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease. Drugs 1997; 53: 299–336.PubMedCrossRefGoogle Scholar
  65. 65.
    Pan HY. Clinical pharmacology of pravastatin, a selective inhibitor of HMG-CoA reductase. Eur J Clin Pharmacol 1991; 40 Suppl. 1:S15–8.PubMedGoogle Scholar
  66. 66.
    Knauf H, Mutschler E. Clinical pharmacokinetics and pharmacodynamics of torasemide. Clin Pharmacokinet 1998; 34: 1–24.PubMedCrossRefGoogle Scholar
  67. 67.
    Schwartz S, Brater DC, Pound D, et al. Bioavailability, pharmacokinetics, and pharmacodynamics of torasemide in patients with cirrhosis. Clin Pharmacol Ther 1993; 54: 90–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Brunner G, von Bergmann K, von Möllendorff 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 Drug Res 1988; 38: 176–9.Google Scholar
  69. 69.
    Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam: therapeutic implications. Clin Pharmacokinet 1993; 24: 453–71.PubMedCrossRefGoogle Scholar
  70. 70.
    Juhl RP, Van Thiel DH, Dittert LW, et al. Alprazolam pharmacokinetics in alcoholic liver disease. J Clin Pharmacol 1984; 24: 113–9.PubMedGoogle Scholar
  71. 71.
    Garzone PD, Krobot PD. Pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet 1989; 16: 337–64.PubMedCrossRefGoogle Scholar
  72. 72.
    Thummel KE, O’shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1996; 59: 491–502.PubMedCrossRefGoogle Scholar
  73. 73.
    Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 1996; 60: 14–24.PubMedCrossRefGoogle Scholar
  74. 74.
    Trouvin JH, Farinotti R, Haberer JP, et al. Pharmacokinetics of midazolam in anaesthetized cirrhotic patients. Br J Anaesth 1988; 60: 762–7.PubMedCrossRefGoogle Scholar
  75. 75.
    MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986; 27: 190–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Pentikäinen PJ, Välisalm L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 1989; 29: 272–7.PubMedGoogle Scholar
  77. 77.
    Kroboth PD, Smith RB, Van Thiel DH, et al. Nighttime dosing of triazolam in patients with liver disease and normal subjects: kinetics and daytime effects. J Clin Pharmacol 1987; 27: 555–60.PubMedGoogle Scholar
  78. 78.
    Bakti G, Fisch HU, Karlaganis G, et al. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology 1987; 7: 629–38.PubMedCrossRefGoogle Scholar
  79. 79.
    Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology 1991; 13 (4): 786–95.PubMedCrossRefGoogle Scholar
  80. 80.
    Brodgen RN, Goa KL, Flumazenil: a reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991; 42: 1061–89.CrossRefGoogle Scholar
  81. 81.
    Janssen U, Walker S, Maier K, et al. Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther 1989; 46: 317–23.PubMedCrossRefGoogle Scholar
  82. 82.
    van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet 1993; 24: 203–20.PubMedCrossRefGoogle Scholar
  83. 83.
    van Harten J. Overview of the pharmacokinetics of fluvoxamine. Clin Pharmacokinet 1995; 29 Suppl. 1: 1–9.PubMedCrossRefGoogle Scholar
  84. 84.
    van Harten J, Duchier J, Devissaguet JP, et al. Pharmacokinetics of fluvoxamine maleate in patients with liver cirrhosis after single-dose oral administration. Clin Pharmacokinet 1993; 24: 177–82.PubMedCrossRefGoogle Scholar
  85. 85.
    Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 1994; 26: 201–14.PubMedCrossRefGoogle Scholar
  86. 86.
    Schenker S, Bergstrom RF, Wolen RL, et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44: 353–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Gunasekara NS, Noble S, Benfield P. Paroxetine: an update of its pharmacology and therapeutic use in depression and a review of its use in other disorders. Drugs 1998; 55: 85–120.PubMedCrossRefGoogle Scholar
  88. 88.
    Krastev Z, Terziivanov D, Vlahov V, et al. The pharmacokinetics of paroxetine in patients with liver cirrhosis. Acta Psychiatr Scand 1989; 80 Suppl. 350: 91–2.CrossRefGoogle Scholar
  89. 89.
    Dahoff K, Almdal TP, Bjerrum K, et al. Pharmacokinetics of paroxetine im patients with cirrhosis. Eur J Clin Pharmacol 1991; 41: 351–4.CrossRefGoogle Scholar
  90. 90.
    Davis R, Whittington R, Bryson HM. Nefazodone: a review of its pharmacology and clinical efficacy in the management of major depression. Drugs 1997; 53: 608–36.PubMedCrossRefGoogle Scholar
  91. 91.
    Barbhaiya RH, Shukla UA, Natarajan XS, et al. Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis. Clin Pharmacol Ther 1995; 58: 390–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Barbhaiya RH, Shukla UA, Greene DS. Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment. Eur J Clin Pharmacol 1995; 49: 221–8.PubMedGoogle Scholar
  93. 93.
    Fitton A, Faulds D, Goa KL. Moclobemide: a review of its pharmacological properties and therapeutic use in depressive illness. Drugs 1992; 43: 561–96.PubMedCrossRefGoogle Scholar
  94. 94.
    Stoeckel K, Pfefen K, Mayersohn M, et al. Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function. Acta Psychiatr Scand 1990; Suppl. 360: 94–7.Google Scholar
  95. 95.
    Adkins JC, Noble S. Tiagabine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy. Drugs 1998; 55: 437–60.PubMedCrossRefGoogle Scholar
  96. 96.
    Lau AH, Gustavson LE, Sperelakis R, et al. Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function. Epilepsia 1997; 38: 448–51.CrossRefGoogle Scholar
  97. 97.
    Lauritsen K, Laursen LS, Rask-Madsen J. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases. Clin Pharmacokinet 1990; 19: 11–31.PubMedCrossRefGoogle Scholar
  98. 98.
    Magueur E, Hagege H, Attali P, et al. Pharmacokinetics of metoclopramide in patients with liver cirrhosis. Br J Clin Pharmacol 1991; 31: 185–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Hellstern A, Hellenbrecht D, Sailer R, et al. Absolute bioavailability of metoclopramide given orally or by enema in patients with normal liver function or with cirrhosis of the liver. Arzneimittel Forschung Drug Res 1987; 37: 733–6.Google Scholar
  100. 100.
    Roila F, Del Favero A. Ondansetron clinical pharmacokinetics. Clin Pharmacokinet 1995; 29: 95–109.PubMedCrossRefGoogle Scholar
  101. 101.
    Blake JC, Palmer JL, Minton NA, et al. The pharmacokinetic of intravenous ondansetron in patients with hepatic impairment. Br J Clin Pharmacol 1993; 35: 441–3.PubMedCrossRefGoogle Scholar
  102. 102.
    Figg WD, Dukes GE, Pritchard JF, et al. Ondansetron (OND) pharmacokinetics in chronic liver disease. Clin Pharmacol Ther 1992; 51: 171.Google Scholar
  103. 103.
    Rhoda Lee C, Plosker GL, McTavish D. Tropisetron: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993; 46: 925–43.CrossRefGoogle Scholar
  104. 104.
    de Bruijn KM. Tropisetron: a review of the clinical experience. Drugs 1992; 43: 11–22.PubMedCrossRefGoogle Scholar
  105. 105.
    Andersson T, Cederberg C, Regärdh CG, et al. Pharmacokinetics of various single intravenous and oral doses of omeprazole. Eur J Clin Pharmacol 1990; 39: 195–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Delhotal-Landes B, Petite JP, Flouvat B. Clinical pharmacokinetics of lansoprazole. Clin Pharmacokinet 1995; 28: 458–70.CrossRefGoogle Scholar
  107. 107.
    Fitton A, Wiseman L. Pantoprazole: a review of its pharmacological properties and therapeutic use in acid-related disorders. Drugs 1996; 51: 460–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Delhotal-Landes B, Flouvat B, Duchier J, et al. Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity. Eur J Clin Pharmacol 1993; 45: 367–71.PubMedCrossRefGoogle Scholar
  109. 109.
    Coste T, Logeais C, Delhotal-Landes B, et al. Pharmacokinetics of lansoprazole after repeated administration in cirrhosis patients [abstract]. Gastroenterology 1993; 104 Suppl.: A59.Google Scholar
  110. 110.
    Brunner G, Chang J, Hartmann M, et al. Pharmacokinetik von pantoprazol bei patienten mit leberzirrhose. Med Klin 1994; 8 Suppl. 1: 189.Google Scholar
  111. 111.
    Benet LZ, Zech K. Pharmacokinetics: a relevant factor for the choice of a drug? Aliment Pharmacol Ther 1994; 8 Suppl. 1: 25–32.PubMedGoogle Scholar
  112. 112.
    Andersson T, Olsson R, Regärdh CG, et al. Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis. Clin Pharmacokinet 1993; 24: 71–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Landahl S, Andersson T, Larsson HE, et al. Pharmacokinetic study of omeprazole in elderly healthy volunteers. Clin Pharmacokinet 1992; 23: 469–76.PubMedCrossRefGoogle Scholar
  114. 114.
    Rinetti M, Regazzi MB, Villani P, et al. Pharmacokinetics of omeprazole in cirrhotic patients. Arzneimittel Forschung Drug Res 1991; 41: 420–2.Google Scholar
  115. 115.
    McKee RF, MacGilchrist AJ, Garden OJ, et al. The antisecretory effect and pharmacokinetics of omeprazole in chronic liver disease. Aliment Pharmacol Ther 1988; 2: 429–37.PubMedCrossRefGoogle Scholar
  116. 116.
    Caulin C, Gouéron H, Bretagne JF, et al. Tolerance de l’omeprazole chez l’insuffisant hepatique. Etude ouverte chez 24 cirrhotiques. Gastroenterol Biol Clin 1987; 11: 42A.Google Scholar
  117. 117.
    Schentag JJ, Cerra FB, Calleri G, et al. Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet 1979 Jan 27; I (8109): 177–81.CrossRefGoogle Scholar
  118. 118.
    Schentag JJ, Cerra FB, Calleri GM, et al. Age, disease, and cimetidine disposition in healthy subjects and chronically ill patients. Clin Pharmacol Ther 1981 Jun; 29 (6): 737–43.PubMedCrossRefGoogle Scholar
  119. 119.
    Vial T, Goubier C, Bergeret A, et al. Side effects of ranitidine. Drug Saf 1991; 6 (2): 94–117.PubMedCrossRefGoogle Scholar
  120. 120.
    Efthymiopoulos C, Bramer SL, Maroli A. Pharmacokinetics of grepafloxacin after oral administration of single and repeated doses in healthy young males. Clin Pharmacokinet 1997; 33 Suppl. 1: 1–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Efthymiopoulos C, Bramer SL, Maroli A, et al. Grepafloxacin pharmacokinetics in individuals with hepatic dysfunction. Clin Pharmacokinet 1997; 33 Suppl. 1: 25–31.PubMedCrossRefGoogle Scholar
  122. 122.
    Lau AH, Lam NP, Piscitelli SC, et al. Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives. Clin Pharmacokinet 1992; 23: 328–64.PubMedCrossRefGoogle Scholar
  123. 123.
    Taburet AM, Delion F, Attali P, et al. Pharmacokinetics of ornidazole in patients with severe liver cirrhosis. Clin Pharmacol Ther 1986; 40: 359–64.PubMedCrossRefGoogle Scholar
  124. 124.
    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: 373–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Bressolle F, Gonçalves F, Gouby A, et al. Pefloxacin clinical pharmacokinetics. Clin Pharmacokinet 1994; 27: 418–46.PubMedCrossRefGoogle Scholar
  126. 126.
    Danan G, Montay G, Cunci R, et al. Pefloxacin kinetics in cirrhosis. Clin Pharmacol Ther 1985; 38: 439–42.PubMedCrossRefGoogle Scholar
  127. 127.
    Galtier M, Bressolle F, de la Coussaye JE, et al. Multiple dose pharmacokinetics of pefloxacin in patients with hepatocellular deficiency. Clin Pharmacokinet 1993; 25: 415–23.PubMedCrossRefGoogle Scholar
  128. 128.
    Cardey J, Silvain C, Bouquet S, et al. Oral pharmacokinetics and ascitic fluid penetration of pefloxacin in cirrhosis. Eur J Clin Pharmacol 1987; 33: 469–72.PubMedCrossRefGoogle Scholar
  129. 129.
    Rana KZ, Dudley MN. Clinical pharmacokinetics of stavudine. Clin Pharmacokinet 1997; 33 (4): 276–84.PubMedCrossRefGoogle Scholar
  130. 130.
    Schaad HJ, Petty BG, Grasela DM, et al. Pharmacokinetics and safety of a single dose of stavudine (d4T) in patients with severe hepatic impairment. Antimicrob Agents Chemother 1997; 41 (12): 2793–6.PubMedGoogle Scholar
  131. 131.
    Grasela D, Christofalo B, Raymond E, et al. Safety and pharmacokinetics (PK) of stavudine (d4T) in subjects with mild, moderate or severe renal impairment [abstract]. 2nd National Conference on Human Retroviruses and Related Infections; 1995 Jan 29–Feb 2; Washington, DC. 145.Google Scholar
  132. 132.
    Acosta EP, Page LM, Fletcher CV. Clinical pharmacokinetics of zidovudine: an update. Clin Pharmacokinet 1996; 30: 251–62.PubMedCrossRefGoogle Scholar
  133. 133.
    Moore KHP, Raasch RH, Bronwer KLR, et al. Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials group protocol 062). Antimicrob Agents Chemother 1995; 39: 2732–7.PubMedCrossRefGoogle Scholar
  134. 134.
    Taburet AM, Naveau S, Zorza G, et al. Pharmacokinetics of zidovudine in patients with liver cirrhosis. Clin Pharmacol Ther 1990; 47: 731–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Bareggi SR, Cinque P, Mazzei M, et al. Pharmacokinetics of zidovudine in HIV-positive patients with liver disease. J Clin Pharmacol 1994; 34: 782–6.PubMedGoogle Scholar
  136. 136.
    Faulds D, Goa KL, Benfield P. Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993; 45: 953–1040.PubMedCrossRefGoogle Scholar
  137. 137.
    Noble S, Markham A. Cyclosporin: a review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation. Drugs 1995; 50: 924–41.PubMedCrossRefGoogle Scholar
  138. 138.
    Kahan BD, Kramer WG, Wideman C, et al. Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation 1986; 41: 459–64.PubMedCrossRefGoogle Scholar
  139. 139.
    Venkataramanan R, Gray J, Ptachcinski RJ, et al. Cyclosporine kinetics in liver disease. Clin Pharmacol Ther 1985; 37: 234.Google Scholar
  140. 140.
    Hebert MF, Walcher VJ, Benet LZ. Cyclosporine pharmacokinetics pre- and post-liver transplantation [abstract]. Clin Pharmacol Ther 1995; 57: 187.Google Scholar
  141. 141.
    Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 29: 404–30.PubMedCrossRefGoogle Scholar
  142. 142.
    Jain AB, Venkataramanan R, Cadoff E, et al. Effect of hepatic dysfunction and T tube clamping on FK506 pharmacokinetics and trough concentrations. Transplant Proc 1990; 22 Suppl. 1: 57–9.PubMedGoogle Scholar
  143. 143.
    Jain AB, Abu-Elmagd K, Abdallah H, et al. Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion. J Clin Pharmacol 1993; 33: 606–11.PubMedGoogle Scholar
  144. 144.
    Winkler M, Ringe B, Rodeck B, et al. The use of plasma levels for FK506 dosing in liver-grafted patients. Transpl Int 1994; 7: 329–33.PubMedCrossRefGoogle Scholar
  145. 145.
    Abu-Elmagd K, Fung JJ, Alessiani M, et al. The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver. Transplantation 1991; 52: 71–7.PubMedCrossRefGoogle Scholar
  146. 146.
    Abu-Elmagd K, Fung JJ, Alessiani M, et al. Strategy of FK506 therapy in liver transplant patients: effect of graft function. Transplant Proc 1991; 23: 2777–80.PubMedGoogle Scholar
  147. 147.
    Christians U, Braun F, Schmidt M, et al. Specific and sensitive measurement of FK506 and its metabolites in blood and urine of liver-graft recipients. Clin Chem 1992; 38: 2025–32.PubMedGoogle Scholar
  148. 148.
    Wiseman LR, Goa KL. Toremifene: a review of its pharmacological properties and clinical efficacy in the management of advanced breast cancer. Drugs 1997; 54: 141–60.PubMedCrossRefGoogle Scholar
  149. 149.
    Anttila M, Laakso S, Nyländen P, et al. Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function. Clin Pharmacol Ther 1995; 57: 628–35.PubMedCrossRefGoogle Scholar
  150. 150.
    Jorga KM, Kroodsma JM, Fotteler B, et al. Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites. Clin Pharmacol Ther 1998; 63 (6): 646–54.PubMedCrossRefGoogle Scholar
  151. 151.
    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 (3): 263–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Chopra S, Griffin PH. Laboratory tests and diagnostic procedures in evaluation of liver disease. Am J Med 1985; 79 (2): 221–30.PubMedCrossRefGoogle Scholar
  153. 153.
    Barbare JC, Poupon RE, Jaillon P, et al. Intrinsic hepatic clearance and Child-Turcotte classification for assessment of liver function in cirrhosis. J Hepatol 1985; 1 (3): 253–9.PubMedCrossRefGoogle Scholar
  154. 154.
    Conn HO. A peek at the Child-Turcotte classification. Hepatology 1981; 1: 673–6.PubMedCrossRefGoogle Scholar
  155. 155.
    Tanaka E. Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease. J Clin Pharm Ther 1998; 23 (3): 161–70.PubMedCrossRefGoogle Scholar
  156. 156.
    Westphal JF, Brogard JM. Drug administration in chronic liver disease. Drug Saf 1997; 17 (1): 47–73.PubMedCrossRefGoogle Scholar
  157. 157.
    Brater DC. Clinical pharmacology of loop diuretics in health and disease. Eur Heart J 1992; 13 Suppl. G: 10–4.PubMedGoogle Scholar
  158. 158.
    Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother 1994; 33 (4): 685–706.PubMedCrossRefGoogle Scholar
  159. 159.
    Chapuis L, Cadranel JF, Nordmann P, et al. Grand mal seizures as a complication of treatment with pefloxacin in patients with cirrhosis: a report of three cases. J Hepatol 1993; 19 (3): 383–4.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Vanni Rodighiero
    • 1
  1. 1.Dipartimento di FarmacologiaUniversità di PadovaPadovaItaly

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