Skip to main content

Advertisement

Log in

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction

  • Review Article
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pond SM, Tozer TN (1984) First-pass elimination: basic concepts and clinical consequences. Clin Pharmacokinet 9:1–15

    PubMed  CAS  Google Scholar 

  2. Danielson PB (2002) The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 3:561–597

    PubMed  CAS  Google Scholar 

  3. Fisher MB, Paine MF, Strelevitz TJ, Wrighton SA (2001) The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab Rev 33:273–297

    PubMed  CAS  Google Scholar 

  4. Morgan DJ, McLean AJ (1995) Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease–an update. Clin Pharmacokinet 29:370–391

    PubMed  CAS  Google Scholar 

  5. Reichen J (1999) The role of the sinusoidal endothelium in liver function. News Physiol Sci 14:117–121

    PubMed  Google Scholar 

  6. Giacomini KM, Sigiyama Y (2006) Membrane transporters and drug response. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New York, pp 41–70

    Google Scholar 

  7. Chandra P, Brouwer KLR (2004) The complexities of hepatic transport: current knowledge and emerging concepts. Pharm Res 21:719–735

    PubMed  CAS  Google Scholar 

  8. Le Couteur DG, Fraser R, Hilmer S, Rivory LP, McLean AJ (2005) The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet 44:187–200

    PubMed  Google Scholar 

  9. Traumer M, Meier PJ, Boyer JL (1999) Molecular regulation of hepatocellular transport systems in cholestatsis. J Hepatol 31:165–178

    Google Scholar 

  10. Rowland M, Benet LZ, Graham GG (1973) Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm 1:123–136

    PubMed  CAS  Google Scholar 

  11. Wilkinson GR (1987) Clearance approaches in pharmacology. Pharmacol Rev 39:1–47

    PubMed  CAS  Google Scholar 

  12. Quigley EMM (1996) Gastrointestinal dysfunction in liver disease and portal hypertension: gut-liver interactions revisited. Dig Dis Sci 41:557–563

    PubMed  CAS  Google Scholar 

  13. Zuckerman MJ, Menzies IS, Ho H, Gregory GG, Casner NA, Crane RS, Hernandez JA (2004) Assessment of intestinal permeability and absorption in cirrhotic patients with ascites using combined sugar probes. Dig Dis Sci 49:621–626

    PubMed  Google Scholar 

  14. Blaschke TF, Rubin PC (1979) Hepatic first-pass metabolism in liver disease. Clin Pharmacokinet 4:423–432

    PubMed  CAS  Google Scholar 

  15. Tam YK (1993) Individual variation in first-pass metabolism. Clin Pharmacokinet 25:300–328

    PubMed  CAS  Google Scholar 

  16. Wilkinson GR (1980) Influence of liver disease on pharmacokinetics. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics–principles of therapeutic drug monitoring. Applied Therapeutics, San Francisco, pp 19–41

    Google Scholar 

  17. Pentikäinen PJ, Neuvonen PJ, Jotell KG (1980) Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver. Eur J Clin Pharmacol 17:275–284

    PubMed  Google Scholar 

  18. Neugebauer G, Gabor M, Reiff K (1988) Pharmacokinetics and bioavailability of carvedilol in patients with liver cirrhosis. Drugs 36(Suppl 6):148–154

    Google Scholar 

  19. Homeida M, Jackson L, Roberts CJC (1978) Decreased first-pass metabolism of labetalol in chronic liver disease. Br Med J 2:1048–1050

    PubMed  CAS  Google Scholar 

  20. Neal EA, Meffin PJ, Gregory PB, Blaschke TF (1979) Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 77:96–102

    PubMed  CAS  Google Scholar 

  21. Regårdh C-G, Jordö L, Lundborg P, Olsson R, Rönn O (1981) Pharmacokinetics of metoprolol in patients with hepatic cirrhosis. Clin Pharmacokinet 6:375–388

    Google Scholar 

  22. Pentikäinen PJ, Välisalmi L, Himberg JL, Crevoisier C (1989) Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 29:272–277

    PubMed  Google Scholar 

  23. Hasselström J, Eriksson S, Persson A, Rane A, Svensson JO, Säwe J (1990) The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 29:289–297

    PubMed  Google Scholar 

  24. Kleinbloesem CH, van Harten J, Wilson JPH, Danhof M, van Brummelen P, Breimer DD (1986) Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration. Clin Pharmacol Ther 40:21–28

    PubMed  CAS  Google Scholar 

  25. van Harten J, van Brummelen P, Wilson JHP, Lodewijks MTM, Breimer DD (1988) Nisoldipine: kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration. Eur J Clin Pharmacol 34:387–394

    PubMed  Google Scholar 

  26. Branch RA, Kornhauser DM, Shand DG, Wilkinson GR, Wood AJJ (1977) Biological determinants of propranolol disposition in normal subjects and patients with cirrhosis. Br J Clin Pharmacol 4:630P

    PubMed  CAS  Google Scholar 

  27. Somogyi A, Albrecht M, Kliems G, Schafer K, Eichelbaum M (1981) Pharmacokinetics, bioavailability and ECH response in patients with liver cirrhosis. Br J Clin Pharmacol 12:51–60

    PubMed  CAS  Google Scholar 

  28. Chalasani N, Gorski JC, Patel NH, Hall SD, Galinsky RE (2001) Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology 34:1103–1108

    PubMed  CAS  Google Scholar 

  29. Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O’Mara EM Jr, Hall SD (1998) The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther 64:133–143

    PubMed  CAS  Google Scholar 

  30. MacKichan JJ (2006) Influence of protein binding and use of unbound (free) drug concentrations. In: Burton ME, Shaw LM, Schentag JJ, Evans WE (eds) Applied pharmacokinetics & pharmacodynamics–principles of therapeutic drug monitoring. Lippincott Williams & Wilkins, Philadelphia, pp 82–120

    Google Scholar 

  31. Blaschke TF (1977) Protein binding and kinetics of drugs in liver disease. Clin Pharmacokinet 2:32–44

    PubMed  CAS  Google Scholar 

  32. el Touny M, el Guinaidy M, Abdel Bary M, Osman L, Sabbour MS (1992) Pharmacokinetics of cefodizime in patients with liver cirrhosis and ascites. Chemotherapy 38:201–205

    PubMed  Google Scholar 

  33. Williams RL, Upton RA, Cello JP, Jones RM, Blitstein M, Kelly J, Nierenburg D (1984) Naproxen disposition in patients with alcoholic cirrhosis. Eur J Clin Pharmacol 27:291–296

    PubMed  CAS  Google Scholar 

  34. Tozer TN (1986) Concepts basic to pharmacokinetics. In: Rowland M, Tucker G (eds) Pharmacokinetics–theory and practice. Pergamon Press, Oxford, pp 29–51

    Google Scholar 

  35. Delcò F, Tchambaz L, Schlienger R, Drewe J, Krähenbühl S (2005) Dosage adjustment in patients with liver disease. Drug Saf 28:529–545

    PubMed  Google Scholar 

  36. Liu L, Pang KS (2004) The roles of transporters and enzymes in hepatic drug processing. Drug Metab Disp 33:1–7

    Google Scholar 

  37. Morgan DJ, McLean AJ (1991) Therapeutic implications of impaired hepatic oxygen diffusion in chronic liver disease. Hepatology 14:1280–1282

    PubMed  CAS  Google Scholar 

  38. George J, Murray M, Byth K et al (1995) Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 21:20–128

    Google Scholar 

  39. George J, Liddle C, Murray M et al (1995) Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. Biochem Pharmacol 49:873–881

    PubMed  CAS  Google Scholar 

  40. Furlan V, Demirdjian S, Bourdon O et al (1999) Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 289:1169–1175

    PubMed  CAS  Google Scholar 

  41. Villeneuve J-P, Pichette V (2004) Cytochrome P450 and liver diseases. Curr Drug Metab 5:273–282

    PubMed  CAS  Google Scholar 

  42. Elbekai RH, Korashy HM, El-Kadi OS (2000) The effect of liver cirrhosis on the regulation and expression of drug metabolising enzymes. Curr Drug Metab 5:157–167

    Google Scholar 

  43. Adedoyin A, Arns PA, Richards WO, Wilkinson GR, Branch RA (1998) Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 64:8–17

    PubMed  CAS  Google Scholar 

  44. Branch RA (1998) Drugs in liver disease (letter to the editor). Clin Pharmacol Ther 64:462–465

    PubMed  CAS  Google Scholar 

  45. Frye RF, Zgheib NK, Matzke GR, Chaves-Gnecco D, Rabinovitz M, Shaikh OS, Branch RA (2006) Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 80:235–245

    PubMed  CAS  Google Scholar 

  46. Daly AK (2006) Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet 45:13–31

    PubMed  CAS  Google Scholar 

  47. Lin YS, Dowling ALS, Quigely SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE (2002) Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62:162–172

    PubMed  CAS  Google Scholar 

  48. Kovarik JM, Sabia HD, Figueiredo J, Zimmermann H, Reynolds C, Dilzer SC, Lasseter K, Rordorf C (2001) Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 70:425–430

    PubMed  CAS  Google Scholar 

  49. Hoyumpa AM, Schenker S (1991) Is glucuronidation truly preserved in patients with liver disease? Hepatology 13:786–795

    PubMed  CAS  Google Scholar 

  50. Levy M, Caraco Y, Geisslinger G (1998) Drug acetylation in liver disease. Clin Pharmacokinet 34:219–226

    PubMed  CAS  Google Scholar 

  51. Shull HJ, Wilkinson GR, Johnson R et al (1976) Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann Intern Med 84:420–425

    PubMed  CAS  Google Scholar 

  52. Kraus JW, Desmond PV, Marshall JP et al (1978) Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther 24:411–419

    PubMed  CAS  Google Scholar 

  53. Ghabrial H, Desmond PV, Watson KJ et al (1986) The effects of age and chronic liver disease on the elimination of temazepam. Eur J Clin Pharmacol 30:93–97

    PubMed  CAS  Google Scholar 

  54. Klotz U, Antonin KH, Brügel H, Bieck PR (1977) Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. Clin Pharmacol Ther 21:430–436

    PubMed  CAS  Google Scholar 

  55. Debinski HS, Lee CS, Danks JA, Mackenzie PI, Desmond PV (1995) Localization of 5′-diphosphate-glucuronosyltransferase in human liver injury. Gastroenterology 108:1464–1469

    PubMed  CAS  Google Scholar 

  56. Mazoit JX, Sandouk P, Scherrmann JM, Roche A (1990) Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther 48:613–618

    PubMed  CAS  Google Scholar 

  57. Crotty B, Watson KJ, Desmond PV et al (1989) Hepatic extraction of morphine is impaired in cirrhosis. Eur J Clin Pharmacol 36:501–506

    PubMed  CAS  Google Scholar 

  58. Macdonald JI, Wallace SM, Mahachai V et al (1992) Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in patients with liver cirrhosis. Eur J Clin Pharmacol 42:471–474

    PubMed  CAS  Google Scholar 

  59. Hildebrand M, Hellstern A, Humpel M et al (1990) Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers. Eur J Drug Metab Pharmacokinet 15:19–26

    PubMed  CAS  Google Scholar 

  60. Sonne J, Anderson PB, Loft S, Dossing M, Andreasen F (1990) Glucuronidation of oxazepam is not spared in patients with hepatic encephalopathy. Hepatology 11:951–956

    PubMed  CAS  Google Scholar 

  61. Marcellin P, de Bony F, Garret C, Altman C, Boige V, Castelnau C, Laurent-Puig C, Trinchet JC, Rolan P, Chen C, Mamet JP, Bidault R (2001) Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol 51:410–414

    PubMed  CAS  Google Scholar 

  62. Taburet AM, Naveau S, Zorza G et al (1990) Pharmacokinetics of zidovudine in patients with liver cirrhosis. Clin Pharmacol Ther 47:731–739

    PubMed  CAS  Google Scholar 

  63. Parker G, Bullingham R, Kamm B et al (1996) Pharmacokinetics of oral mycophenolate mofetil in volunteer subjects with varying degrees of hepatic oxidative impairment. J Clin Pharmacol 36:332–344

    PubMed  CAS  Google Scholar 

  64. Furlan V, Demirdjian S, Bourdon O, Magdalou J, Taburet A-M (1999) Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 289:1169–1175

    PubMed  CAS  Google Scholar 

  65. Congiu M, Mashford ML, Slavin JL, Desmond PV (2002) UDP glucuronosyltransferase mRNA levels in human liver disease. Drug Metab Disp 30:129–134

    CAS  Google Scholar 

  66. Zamek-Gliszczynski MJ, Hofmaster KA, Nezasa K, Tallman MN, Brouwer KL (2006) Integration of hepatic drug transporters and phase II metabolizing enzymes: mechanisms of hepatic excretion of sulphate, glucuronide and glutathione metabolites. Eur J Pharm Sci 27:447–486

    PubMed  CAS  Google Scholar 

  67. Lam JL, Okochi H, Huang Y, Benet LZ (2006) In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay. Drug Metab Disp 34:1336–1344

    CAS  Google Scholar 

  68. Klaassen CD, Watkins JB III (1984) Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol Rev 36:1–67

    PubMed  CAS  Google Scholar 

  69. Mortimer PR, Mackie DB, Haynes S (1969) Ampicillin levels in human bile in the presence of biliary tract disease. Br Med J 3:88–89

    PubMed  CAS  Google Scholar 

  70. Sales JEL, Sutcliffe M, O’Grady F (1972) Cephalexin levels in human bile in the presence of biliary tract disease. Br Med J 3:441–442

    PubMed  CAS  Google Scholar 

  71. Brown RB, Martyak SN, Barza M, Curtis L, Weinstein L (1976) Penetration of clindamycin phosphate into the abnormal human biliary tract. Ann Intern Med 84:168–170

    PubMed  CAS  Google Scholar 

  72. Leung JWC, Chan RCY, Cheung SW, Sung JY, Chung SCS, French GL (1990) The effect of obstruction on the biliary excretion of cefoperazone and ceftazidime. J Antimicrob Chemother 25:399–406

    PubMed  CAS  Google Scholar 

  73. van Delden OM, van Leeuwen DJ, Jansen PLM, Hoek FJ, Huibregtse K, Tytgat GNJ (1994) Biliary excretion of ceftriaxon in non-stagnant and stagnant bile. J Antimicrob Chemother 33:193–194

    PubMed  Google Scholar 

  74. van den Hazel SJ, de Vries XH, Speelman P, Dankert J, Tytgat GNJ, Huibregtse K, van Leeuwen DJ (1996) Biliary excretion of ciprofloxacin and piperacillin in the obstructed biliary tract. Antimicrob Agents Chemother 40:2658–2660

    Google Scholar 

  75. Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, Stauber RE, Krejs GJ, Denk H, Zatloukal K, Trauner M (2001) Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33:633–646

    PubMed  CAS  Google Scholar 

  76. Kullak-Ublick GA, Baretton GB, Oswald M, Renner EL, Paumgartner G, Beuers U (2002) Expression of the heaptocyte canalicular multidrug resistant protein (MRP2) in primary biliary cirrhosis. Hepatol Res 23:78–82

    PubMed  CAS  Google Scholar 

  77. Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall H-U, Zatloukal K, Denk H Tranner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727

    PubMed  CAS  Google Scholar 

  78. Gonzales G, Aransibia A, Rivas MI, Caro P, Antezana C (1982) Pharmacokinetics of frusemide in patients with hepatic cirrhosis. Eur J Clin Pharmacol 22:315–320

    Google Scholar 

  79. Marantonio LA, Auls WHR, Murdoch WR, Purohit R, Skellern GG, Howes CA (1983) The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease. Br J Clin Pharmacol 25:245–252

    Google Scholar 

  80. Cello JP, Oie S (1983) Cimetidine disposition in patients with Laennec’s cirrhosis during multiple dosing therapy. Eur J Clin Pharmacol 25:223–229

    PubMed  CAS  Google Scholar 

  81. Smith IL, Ziemniak JA, Bernhard H, Eshelman FN, Martin LE, Schentagg JJ (1984) Ranitidine disposition and systemic availability in hepatic cirrhosis. Clin Pharmacol Ther 35:487–494

    PubMed  CAS  Google Scholar 

  82. Brockmöller J, Thomsen T, Wittstock M, Coupez R, Lochs H, Roots I (2005) Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests. Clin Pharmacol Ther 77:529–541

    PubMed  Google Scholar 

  83. Orlando R, Mussap M, Plebani M et al (2002) Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem 48:850–858

    PubMed  CAS  Google Scholar 

  84. Proulx NL, Akbari A, Garg AX, Rostom A, Jaffey J, Clark HD (2005) Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis. Nephrol Dial Transplant 20:1617–1622

    PubMed  CAS  Google Scholar 

  85. Papadakis MA, Arieff AI (1987) Unpredictability of clinical evaluation of renal function in cirrhosis. Am J Med 82:945–952

    PubMed  CAS  Google Scholar 

  86. Granneman GR, Mahr G, Locke C, Nickel P, Kirch W, Fabian W, Kinzig M, Naber KG, Sörgel F (1992) Pharmacokinetics of temafloxacin in patients with liver impairment. Clin Pharmacokinet 22(Suppl 1):24–32

    PubMed  CAS  Google Scholar 

  87. Caregaro L, Menon F, Angeli P, Amodia P, Merkel C, Bortoluzzi A, Alberino F, Gatta A (1994) Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 154:201–205

    PubMed  CAS  Google Scholar 

  88. Caujolle B, Ballet F, Poupon R (1988) Relationships among beta-adrenergic blockade, propranolol concentration, and liver function in patients with cirrhosis. Scand J Gastroenterol 23:925–930

    PubMed  CAS  Google Scholar 

  89. Ramond MJ, Comoy E, Lebrec D (1986) Alterations in isoprenaline sensitivity in patients with cirrhosis: evidence of abnormality of the sympathetic nervous activity. Br J Clin Pharmacol 21:191–196

    PubMed  CAS  Google Scholar 

  90. Gerbes AL, Remien J, Jungst D, Sauerbruch Y, Paumgartner G (1986) Evidence for down-regulation of beta-2-adrenoceptors in cirrhosis patients with severe cirrhosis. Lancet 1:1409–1411

    PubMed  CAS  Google Scholar 

  91. Janku I, Perlik F, Tkaczykova M, Brodanova M (1992) Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects. Eur J Clin Pharmacol 42:337–340

    PubMed  CAS  Google Scholar 

  92. Keller E, Hoppe-Seyler G, Mumm R, Schollmeyer P (1981) Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide. Eur J Clin Pharmacol 20:27–33

    PubMed  CAS  Google Scholar 

  93. Villeneuve JP, Verbeeck RK, Wilkinson GR, Branch RA (1986) Furosemide kinetics and dynamics in cirrhosis. Clin Pharmacol Ther 40:14–20

    PubMed  CAS  Google Scholar 

  94. Dao MT, Villeneuve JP (1988) Kinetics and dynamics of triamterene at steady-state in patients with cirrhosis. Clin Invest Med 11:6–9

    PubMed  CAS  Google Scholar 

  95. Villeneuve JP, Rocheleau F, Raymond G (1984) Triamterene kinetics and dynamics in cirrhosis. Clin Pharmacol Ther 35:831–837

    PubMed  CAS  Google Scholar 

  96. Schwartz S, Brater DC, Pound D, Green PK, Kramer WG, Rudy D (1993) Bioavailability, pharmacokinetics and pharmacodynamics of torasemide in patients with cirrhosis. Clin Pharmacol Ther 54:90–97

    PubMed  CAS  Google Scholar 

  97. Gentilini P, La Villa G, Marra F, Carloni V, Melani L, Foschi M, Cotrozzi G, Quartini M, Chibbaro G, Tommassi AC, Bernareggi A, Simoni A, Buzzelli G, Laffi G (1996) Pharmacokinetics and pharmacodynamics of torasemide and furosemide in patients with diuretic resistant ascites. J Hepatol 25:481–490

    PubMed  CAS  Google Scholar 

  98. Marcantonio LA, Auld WHR, Murdoch WR, Purohit R, Skellern GG, Howes CA (1983) The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease. Br J Clin Pharmacol 15:245–252

    PubMed  CAS  Google Scholar 

  99. Bakti G, Fisch HU, Karlaganis G, Minder C, Bircher J (1987) Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology 7:629–638

    PubMed  CAS  Google Scholar 

  100. MacGilchrist AJ, Birnie GG, Cook A, Scobie G, Murray T, Watkinson G, Brodie MJ (1986) Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 27:190–195

    PubMed  CAS  Google Scholar 

  101. Davis M (2007) Cholestasis and endogenous opioids – liver disease and endogenous opioid pharmacokinetics. Clin Pharmacokinet 46:825–850

    PubMed  CAS  Google Scholar 

  102. Ahboucha S, Pomier-Layrargues G, Butterworth RF (2004) Increased brain concentrations of endogenous (non-benzodiazepine) GABA-A receptor ligands in human hepatic encephalopathy. Metab Brain Dis 19:241–251

    PubMed  CAS  Google Scholar 

  103. Gines P, Arrovo V, Rodes J (1992) Pharmacotherapy of ascites associated with cirrhosis. Drugs 43:316–332

    PubMed  CAS  Google Scholar 

  104. Roussat J, Maillard M, Nussberger J et al (1999) Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 66:76–84

    Google Scholar 

  105. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649

    PubMed  CAS  Google Scholar 

  106. Wiesner R, Edwards E, Freeman R et al (2003) Model for end-stage liver disease (MELD) and allocation of donor livers. Gasroenterology 124:91–96

    Google Scholar 

  107. Cholongitas E, Marelli L, Shusang V et al (2006) A systematic review of the performance of the model for end-stage liver disease (MELD) in the setting of liver transplantation. Liver Transpl 12:1049–1061

    PubMed  Google Scholar 

  108. Brockmöller J, Roots I (1994) Assessment of liver metabolic function. Clin Pharmacokinet 27:216–248

    Article  PubMed  Google Scholar 

  109. Burra P, Masier A (2004) Dynamic tests to study liver function. Eur Rev Med Pharmacol Sci 8:19–21

    PubMed  CAS  Google Scholar 

  110. Soons PA, De Boer A, Cohen AF, Breimer DD (1991) Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green. Br J Clin Pharmacol 32:697–704

    PubMed  CAS  Google Scholar 

  111. Faybik P, Hetz H (2006) Plasma disappearance rate of indocyanine green in liver dysfunction. Transplant Proc 38:801–802

    PubMed  CAS  Google Scholar 

  112. Keiding S (1987) Hepatic clearance and liver blood flow. J Hepatol 4:393–398

    PubMed  CAS  Google Scholar 

  113. Zeeh J, Lange H, Bosch J, Pohl S, Loesgen H, Eggers R, Navasa M, Chesta J, Bircher J (1988) Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroeneterology 95:749–759

    CAS  Google Scholar 

  114. Molino G, Avagnina P, Belforte G, Bircher J (1998) Assessment of the hepatic circulation in humans: new concepts based on evidence derived from a D-sorbitol clearance method. J Lab Clin Med 131:393–405

    PubMed  CAS  Google Scholar 

  115. Fabre D, Bressolle F, Gomeni R, Bouvet O, Dubois A, Raffanel C, Gris JC, Galtier M (1993) Identification of patients with impaired hepatic drug metabolism using a limited sampling procedure for estimation of phenazone (antipyrine) pharmacokinetic parameters. Clin Pharmacokinet 24:333–343

    PubMed  CAS  Google Scholar 

  116. Renner E, Wietholtz H, Huguenin P, Arnaud MJ, Preisig R (1984) Caffeine: a model compound for measuring liver function. Hepatology 4:38–46

    PubMed  CAS  Google Scholar 

  117. Rogers JF, Rocci ML, Haughey DB, Bertino JS (2003) An evaluation of the suitability of intravenous midazolam as an in vivo marker for hepatic cytochrome P4503A activity. Clin Pharmacol Ther 73:153–158

    PubMed  CAS  Google Scholar 

  118. Engel G, Hofmann U, Heidemann H, Cosme J, Eichelbaum (1996) Antipyrine as a probe for human oxidative metabolism: identification of the cytochrome P50 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther 59:613–623

    PubMed  CAS  Google Scholar 

  119. Armuzzi A, Candelli M, Zocco MA, Andreoli A, De Lorenzo A, Nista EC, Miele L, Cremonini F, Cazzato IA, Grieco A, Gasbarrini G, Gasbarrini A (2002) Review article: breath testing for human liver assessment. Aliment Pharmacol Ther 16:1977–1996

    PubMed  CAS  Google Scholar 

  120. Villeneuve JP, Infante-Rivard C, Ampelas M, Pomier-Layrargues G, Huet PM, Marleau D (1986) Prognostic value of the aminopyrine breath test in cirrhotic patients. Hepatology 6:928–931

    PubMed  CAS  Google Scholar 

  121. Kinirons M, O’Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ, Wilkinson GR (1999) Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther 66:224–31

    PubMed  CAS  Google Scholar 

  122. Rivory LP, Slaviero KA, Hoskins JM, Clarke SJ (2001) The erythromycin breath test for prediction of drug clearance. Clin Pharmacokinet 40:151–158

    PubMed  CAS  Google Scholar 

  123. Kurnik D, Wood AJJ, Wilkinson GR (2006) The erythromycin breath test reflects P-glycoprotein function indepently of cytochrome P450 3A activity. Clin Pharmacol Ther 80:228–234

    PubMed  CAS  Google Scholar 

  124. Lan LB, Dalton JT, Schuetz EG (2000) Mdr1 limits CYP3A metabolism in vivo. Mol Pharmacol 58:863–869

    PubMed  CAS  Google Scholar 

  125. Oellerich M, Armstrong VW (2001) The MEGX test: a tool for the real-time assessment of hepatic function. Ther Drug Monit 23:81–92

    PubMed  CAS  Google Scholar 

  126. Orlando R, Piccoli P, De Martin S, Padrini R, Floreani M, Palatini P (2004) Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo. Clin Pharmacol Ther 75:80–88

    PubMed  CAS  Google Scholar 

  127. Huang YS, Lee SD, Deng JF, Xu JC, Lu RH, Lin YF, Wang Yj, Lo KJ (1993) Measuring lidocaine metabolite monoethylglycinexylidide as a quantitative index of hepatic function in adults with chronic hepatitis and cirrhosis. J Hepatol 19:140–147

    PubMed  CAS  Google Scholar 

  128. Meyer-Wyss B, Renner E, Luo H, Scholer A (1993) Assessment of lidocaine metabolite function in comparison with other quantitative liver function tests. J Hepatol 19:133–139

    PubMed  CAS  Google Scholar 

  129. Kawasaki S, Immamura H, Bandai Y, Sanjo K, Idezuki Y (1992) Direct evidence for the intact hepatocyte theory in patients with liver cirrhosis. Gastroenterology 102:1351–1355

    PubMed  CAS  Google Scholar 

  130. Colli A, Buccino G, Cocciolo M, Parravicini R, Scaltrini G (1988) Disposition of a flow-limited drug (lidocaine) and a metabolic capacity limited drug (theophylline) in liver cirrhosis. Clin Pharmacol Ther 44:642–649

    PubMed  CAS  Google Scholar 

  131. FDA (2003) Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labelling. http://www.fda.gov/cber/gdlns/imphep.pdf. Accessed 16 August 2008

  132. EMEA (2005) Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. http://www.emea.europa.eu/pdfs/human/ewp/23390en.pdf. Accessed 16 August 2008

  133. Spray JW, Willett K, Chase D, Sindelar R, Connelly S (2007) Dosage adjustment for hepatic dysfunction based on Child-Pugh scores. Am J Health-Syst Pharm 64:690–693

    PubMed  Google Scholar 

  134. Hebert MF (1998) Guide to drug dosage in hepatic disease. In:Holford N (ed) Drug data handbook, 3rd edn. Adis International, Auckland, pp 121–179

  135. Sokol SI, Cheng A, Prishman WH, Kaza CS (2000) Cardiovascular drug therapy in patients with hepatic diseases and patients with congestive heart failure. J Clin Pharmacol 40:11–30

    PubMed  CAS  Google Scholar 

  136. Klotz U (2007) Antiarrhythmics – elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet 46:985–996

    PubMed  CAS  Google Scholar 

  137. Davis M (2007) Cholestasis and endogenous opioids: liver disease and exogenous pioid pharmacokinetics. Clin Pharmacokinet 46:825–850

    PubMed  CAS  Google Scholar 

  138. Tegeder I, Lötsch J, Geisslinger G (1999) Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 37:17–40

    PubMed  CAS  Google Scholar 

  139. McCabe SM, Ma Q, Slish JC, Catanzaro LM, Sheth N, DiCenzo R, Morse GD (2008) Antiretroviral therapy – pharmacokinetic considerations in patients with renal or hepatic impairment. Clin Pharmacokinet 47:153–172

    PubMed  CAS  Google Scholar 

  140. Rodighiero V (1999) Effect of liver disease on pharmacokinetics – an update. Clin Pharmacokinet 37:399–431

    PubMed  CAS  Google Scholar 

  141. Kashuba ADM, Park JJ, Persky AM, Brouwer KLR (2006) Drug metabolism, transport, and the influence of hepatic disease. In: Burton ME, Shaw LM, Schentag JJ, Evans WE (eds) Applied pharmacokinetics & pharmacodynamics–principles of therapeutic drug monitoring. Lippincott Williams & Wilkins, Philadelphia, pp 121–164

    Google Scholar 

  142. Tchambaz L, Schlatter C, Jakob M, Krâhenbûhl A, Wolf P, Krâhenbûhl S (2006) Dose adaptation of antineoplastic drugs in patients with liver disease. Drug Saf 29:509–522

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roger K. Verbeeck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verbeeck, R.K. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 64, 1147–1161 (2008). https://doi.org/10.1007/s00228-008-0553-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-008-0553-z

Keywords

Navigation