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Drug Safety

, Volume 32, Issue 7, pp 561–578 | Cite as

Pharmacokinetic Changes of Psychotropic Drugs in Patients with Liver Disease

Implications for Dose Adaptation
  • Chantal Schlatter
  • Sabin S. Egger
  • Lydia Tchambaz
  • Stephan Krähenbühl
Review Article

Abstract

Dose adjustment of psychotropic drugs in patients with liver cirrhosis may be important as most of these drugs are predominantly eliminated by the liver and many of them are associated with dose-dependent adverse reactions. As no surrogate parameter is available to predict hepatic metabolism of drugs, dose adjustment according to pharmacokinetic properties of the drugs is proposed. Psychotropic drugs (antiepileptics, antiparkinsonian drugs, psycholeptics such as antipsychotics, anxiolytics, sedatives and hypnosedatives, and psychoanaleptics such as antidepressants, psychostimulants and antidementia drugs) marketed in Switzerland in 2006 were therefore classified according to their hepatic extraction and/or bioavailability to predict their kinetic behaviour in patients with cirrhosis. The expected changes in hepatic metabolism predicted by pharmacokinetic properties were compared with the results from kinetic studies carried out in patients with liver disease. These studies were identified using MEDLINE searches.

Of the 116 psychotropic drugs available on the Swiss market by the year 2006, only 12 were predominantly eliminated through the kidney. For five substances, no Q0 value (the dose fraction metabolized or excreted extrarenally) could be determined because of lack of pharmacokinetic data. Of 99 drugs with predominant hepatic metabolism, 29.3% were categorized as high, 25.2% as intermediate and 38.4% as low extraction drugs, while seven substances could not be classified. Pharmacokinetic studies in patients with liver disease were available for 55 of these 99 drugs eliminated predominantly by the liver (Q0-value ≥ 0.5). Only a few kinetic studies in patients with liver disease were found for antipsychotics, antiparkinsonian drugs and antidepressants, except for selective serotonin reuptake inhibitors and some newer antidepressants. The expected changes in pharmacokinetics were generally in good agreement with the changes reported in pharmacokinetic studies. For 12 drugs, the observed changes in pharmacokinetics from clinical studies were different from the changes expected based on their classification. However, for low extraction drugs metabolized by cytochrome P450 isozymes, clearance may be reduced by up to 50%.

In conclusion, the classification of drugs according to their hepatic extraction and/or bioavailability is a useful tool for dose adjustment, if information from clinical studies is lacking. There is a gap in information about pharmacokinetic changes in patients with liver cirrhosis for a large number of centrally acting drugs. Kinetic studies for centrally acting drugs with predominant hepatic metabolism should be carried out in patients with liver disease to allow precise dose recommendations for enhanced patient safety.

Keywords

Liver Cirrhosis Psychotropic Drug Cabergoline Oxcarbazepine Hepatic Clearance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was supported by a grant from the Swiss National Science Foundation to Professor Stephan Krähenbühl (310000-112483). ## None of the authors have any conflicts of interest that are directly relevant to the content of this review. The funding organisation had no influence on the study design, analysis and interpretation of data or writing of the review. The authors all contributed equally to this work.

Supplementary material

40264_2012_32070561_MOESM1_ESM.pdf (550 kb)
Supplementary material, approximately 563 KB.

References

  1. 1.
    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991 Jul; 21(1): 42–69PubMedCrossRefGoogle Scholar
  2. 2.
    Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet 1995 Nov; 29(5): 370–91PubMedCrossRefGoogle Scholar
  3. 3.
    Williams RL, Mamelok RD. Hepatic disease and drug pharmacokinetics. Clin Pharmacokinet 1980 Nov–Dec; 5(6): 528–47PubMedCrossRefGoogle Scholar
  4. 4.
    Delco F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf 2005; 28(6): 529–45PubMedCrossRefGoogle Scholar
  5. 5.
    Herbert MF. Guide to drug dosage in hepatic disease. In: Holford NHG, editor. Drug data handbook. 3rd ed. Auckland: Adis International, 1998: 179Google Scholar
  6. 6.
    Westphal JF, Brogard JM. Drug administration in chronic liver disease. Drug Saf 1997 Jul; 17(1): 47–73PubMedCrossRefGoogle Scholar
  7. 7.
    Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci 1998 Oct; 20(5): 183–92PubMedCrossRefGoogle Scholar
  8. 8.
    Rodighiero V. Effects of liver disease on pharmacokinetics: an update. Clin Pharmacokinet 1999 Nov; 37(5): 399–431PubMedCrossRefGoogle Scholar
  9. 9.
    Tchambaz L, Schlatter C, Jakob M, et al. Dose adaptation of antineoplastic drugs in patients with liver disease. Drug Saf 2006; 29(6): 509–22PubMedCrossRefGoogle Scholar
  10. 10.
    Blendis L, Wong F. The hyperdynamic circulation in cirrhosis: an overview. Pharmacol Ther 2001 Mar; 89(3): 221–31PubMedCrossRefGoogle Scholar
  11. 11.
    Krahenbuhl S, Marti U, Grant I, et al. Characterization of mechanisms causing hypoalbuminemia in rats with long-term bile duct ligation. J Hepatol 1995 Jul; 23(1): 79–86PubMedCrossRefGoogle Scholar
  12. 12.
    Butler JM, Begg EJ. Free drug metabolic clearance in elderly people. Clin Pharmacokinet 2008; 47(5): 297–321PubMedCrossRefGoogle Scholar
  13. 13.
    Crone CC, Gabriel GM, DiMartini A. An overview of psychiatric issues in liver disease for the consultationliaison psychiatrist. Psychosomatics 2006 May–Jun; 47(3): 188–205PubMedCrossRefGoogle Scholar
  14. 14.
    Lucena MI, Andrade RJ, Tognoni G, et al. Drug use for non-hepatic associated conditions in patients with liver cirrhosis. Eur J Clin Pharmacol 2003 May; 59(1): 71–6PubMedGoogle Scholar
  15. 15.
    Morgan MH, Read AE. Antidepressants and liver disease. Gut 1972 Sep; 13(9): 697–701PubMedCrossRefGoogle Scholar
  16. 16.
    Documed AG. Arzneimittelkompendium der Schweiz [online]. Available from: http://www.kompendium.ch [Accessed 2009 Mar 16]
  17. 17.
    Murray L. editor. Physicians’ desk reference (PDR). 59th ed. Montvale (NJ): Thomson PDR, 2005Google Scholar
  18. 18.
    Dollery C. editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone, 1999Google Scholar
  19. 19.
    Thomson Healthcare. Micromedex(R) healthcare series [online]. Available from: http://www.thomsonhc.com [Accessed 2009 Mar 16]
  20. 20.
    Speight TM, Holford NHG, editors. Avery’s drug treatment. 4th ed. Auckland: Adis International, 1997Google Scholar
  21. 21.
    Thummel KE, Shen DD, Isoherranen N, et al. Design and optimization of dosage regimens: pharmacokinetic data. In: Brunton LL, editor. Goodman & Gilman’s: the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006Google Scholar
  22. 22.
    Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia (PA): Lippincott Williams & Wilkins, 1999Google Scholar
  23. 23.
    Bénichou C, editor. Adverse drug reactions: a practical guide to diagnosis and management. Chichester: John Wiley & Sons Ltd, 1994Google Scholar
  24. 24.
    Bircher J, Sommer W. Klinisch-pharmakologische Datensammlung. 2. Auflage ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 1999Google Scholar
  25. 25.
    Buckley PF. Receptor-binding profiles of antipsychotics: clinical strategies when switching between agents. J Clin Psychiatry 2007; 68 Suppl. 6: 5–9PubMedGoogle Scholar
  26. 26.
    Trindade E, Menon D, Topfer LA, et al. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ 1998 Nov 17; 159(10): 1245–52PubMedGoogle Scholar
  27. 27.
    Nisoli E, Carruba MO. An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action. Obes Rev 2000 Oct; 1(2): 127–39PubMedCrossRefGoogle Scholar
  28. 28.
    Hvidberg EF, Dam M. Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1(3): 161–88PubMedCrossRefGoogle Scholar
  29. 29.
    Bachmann K, He Y, Sarver JG, et al. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica 2003 Mar; 33(3): 265–76PubMedCrossRefGoogle Scholar
  30. 30.
    Seree EJ, Pisano PJ, Placidi M, et al. Identification of the human and animal hepatic cytochromes P450 involved in clonazepam metabolism. Fundam Clin Pharmacol 1993; 7(2): 69–75PubMedCrossRefGoogle Scholar
  31. 31.
    May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet 2003; 42(12): 1023–42PubMedCrossRefGoogle Scholar
  32. 32.
    DeVane CL. Pharmacokinetics drug interactions, and tolerability of valproate. Psychopharmacol Bull 2003; 37 Suppl. 2: 25–42PubMedGoogle Scholar
  33. 33.
    Lau AH, Gustavson LE, Sperelakis R, et al. Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function. Epilepsia 1997 Apr; 38(4): 445–51PubMedCrossRefGoogle Scholar
  34. 34.
    Deleu D, Northway MG, Hanssens Y. Clinical pharma-cokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet 2002; 41(4): 261–309PubMedCrossRefGoogle Scholar
  35. 35.
    Kvernmo T, Hartter S, Burger E. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 2006 Aug; 28(8): 1065–78PubMedCrossRefGoogle Scholar
  36. 36.
    Taavitsainen P, Anttila M, Nyman L, et al. Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes. Pharmacol Toxicol 2000 May; 86(5): 215–21PubMedCrossRefGoogle Scholar
  37. 37.
    Yoshii K, Kobayashi K, Tsumuji M, et al. Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes. Life Sci 2000; 67(2): 175–84PubMedCrossRefGoogle Scholar
  38. 38.
    Wojcikowski J, Pichard-Garcia L, Maurel P, et al. Contribution of human cytochrome p-450 isoforms to the metabolism of the simplest phenothiazine neuro-leptic promazine. Br J Pharmacol 2003 Apr; 138(8): 1465–74PubMedCrossRefGoogle Scholar
  39. 39.
    Mauri MC, Volonteri LS, Colasanti A, et al. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet 2007; 46(5): 359–88PubMedCrossRefGoogle Scholar
  40. 40.
    Eiermann B, Engel G, Johansson I, et al. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol 1997 Nov; 44(5): 439–46PubMedCrossRefGoogle Scholar
  41. 41.
    DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 2001; 40(7): 509–22PubMedCrossRefGoogle Scholar
  42. 42.
    Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 2000 May; 38(5): 393–14PubMedCrossRefGoogle Scholar
  43. 43.
    Sporkert F, Augsburger M, Giroud C, et al. Determination and distribution of clotiapine (Entumine) in human plasma, post-mortem blood and tissue samples from clotia-pine-treated patients and from autopsy cases. Forensic Sci Int 2007 Aug 6; 170(2-3): 193–9PubMedCrossRefGoogle Scholar
  44. 44.
    Venkatakrishnan K, Greenblatt DJ, Von Moltke LL, et al. Alprazolam is another substrate for human cytochrome P450-3A isoforms [letter]. J Clin Psychopharmacol 1998 Jun; 18(3): 256PubMedCrossRefGoogle Scholar
  45. 45.
    Simons FE, Watson WT, Chen XY, et al. The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis. J Clin Pharmacol 1989 Sep; 29(9): 809–15PubMedGoogle Scholar
  46. 46.
    Kilicarslan T, Haining RL, Rettie AE, et al. Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4. Drug Metab Dispos 2001 Apr; 29 (4 Pt 1): 460–5PubMedGoogle Scholar
  47. 47.
    Von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 1996 Feb; 276(2): 370–9Google Scholar
  48. 48.
    Hellstern A, Hildebrand M, Humpel M, et al. Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique. Int J Clin Pharmacol Ther Toxicol 1990 Jun; 28(6): 256–61PubMedGoogle Scholar
  49. 49.
    Gaillot J, Le Roux Y, Houghton GW, et al. Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency. Sleep 1987; 10 Suppl. 1: 7–21PubMedGoogle Scholar
  50. 50.
    Langtry HD, Benfield P. Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990 Aug; 40(2): 291–313PubMedCrossRefGoogle Scholar
  51. 51.
    Akutsu T, Kobayashi K, Sakurada K, et al. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos 2007 Jan; 35(1): 72–8PubMedCrossRefGoogle Scholar
  52. 52.
    Ganes DA, Midha KK. Identification in in vivo acetylation pathway for N-dealkylated metabolites of doxylamine in humans. Xenobiotica 1987 Aug; 17(8): 993–9PubMedCrossRefGoogle Scholar
  53. 53.
    Koyama E, Chiba K, Tani M, et al. Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. J Pharmacol Exp Ther 1997 Jun; 281(3): 1199–210PubMedGoogle Scholar
  54. 54.
    Eap CB, Bender S, Gastpar M, et al. Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients. Ther Drug Monit 2000 Apr; 22(2): 209–14PubMedCrossRefGoogle Scholar
  55. 55.
    Knapp DR, Gaffney TE, McMahon RE, et al. Studies of human urinary and biliary metabolites of nortriptyline with stable isotope labeling. J Pharmacol Exp Ther 1972 Mar; 180(3): 784–90PubMedGoogle Scholar
  56. 56.
    Brachtendorf L, Jetter A, Beckurts KT, et al. Cytochrome P450 enzymes contributing to demethylation of maprotiline in man. Pharmacol Toxicol 2002 Mar; 90(3): 144–9PubMedCrossRefGoogle Scholar
  57. 57.
    Grasmader K, Verwohlt PL, Rietschel M, et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol 2004 Jul; 60(5): 329–36PubMedCrossRefGoogle Scholar
  58. 58.
    DeVane CL, Liston HL, Markowitz JS. Clinical pharma-cokinetics of sertraline. Clin Pharmacokinet 2002; 41(15): 1247–66PubMedCrossRefGoogle Scholar
  59. 59.
    Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 2007; 46(4): 281–90PubMedCrossRefGoogle Scholar
  60. 60.
    Bonnet U. Moclobemide: evolution, pharmacodynamic, and pharmacokinetic properties. CNS Drug Rev 2002 Fall; 8(3): 283–308PubMedCrossRefGoogle Scholar
  61. 61.
    Mihara K, Otani K, Tybring G, et al. The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients. J Clin Psychopharmacol 1997 Dec; 17(6): 467–71PubMedCrossRefGoogle Scholar
  62. 62.
    Fleishaker JC. Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression. Clin Pharmacokinet 2000 Dec; 39(6): 413–27PubMedCrossRefGoogle Scholar
  63. 63.
    Westra P, van Thiel MJ, Vermeer GA, et al. Pharmacokinetics of galanthamine (a long-acting anticholinesterase drug) in anaesthetized patients. Br J Anaesth 1986 Nov; 58(11): 1303–7PubMedCrossRefGoogle Scholar
  64. 64.
    Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002; 41(10): 719–39PubMedCrossRefGoogle Scholar
  65. 65.
    Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer’s disease. Drugs 2006; 66(11): 1515–34PubMedCrossRefGoogle Scholar
  66. 66.
    Abernethyl DR, Divoll M, Greenblatt DJ, et al. Absolute bioavailability of imipramine: influence of food. Psychopharmacology (Berl) 1984; 83(1): 104–6CrossRefGoogle Scholar
  67. 67.
    Blin O. The pharmacokinetics of pergolide in Parkinson’s disease. Curr Opin Neurol 2003 Dec; 16 Suppl. 1: S9–12PubMedCrossRefGoogle Scholar
  68. 68.
    Reynolds Jr NC, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology 1981 Apr; 31(4): 480–4PubMedCrossRefGoogle Scholar
  69. 69.
    Chounta A, Tsiodras S, Zouridakis S, et al. Sibutramine use associated with reversible hepatotoxicity. Ann Intern Med 2005 Nov 15; 143(10): 763–4PubMedGoogle Scholar
  70. 70.
    Mehta H, Murray B, LoIudice TA. Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride. J Clin Gastroenterol 1984 Apr; 6(2): 149–51PubMedCrossRefGoogle Scholar
  71. 71.
    Farago F. Trigeminal neuralgia: its treatment with two new carbamazepine analogues. Eur Neurol 1987; 26(2): 73–83PubMedCrossRefGoogle Scholar
  72. 72.
    Chitturi S, George J. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, anti-hypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs. Semin Liver Dis 2002; 22(2): 169–83PubMedCrossRefGoogle Scholar
  73. 73.
    Kellermann K, Soditt V, Rambeck B, et al. Fatal hepatotoxicity in a child treated with vigabatrin. Acta Neurol Scand 1996 May; 93(5): 380–1PubMedCrossRefGoogle Scholar
  74. 74.
    Sauve G, Bresson-Hadni S, Prost P, et al. Acute hepatitis after lamotrigine administration. Dig Dis Sci 2000 Sep; 45(9): 1874–7PubMedCrossRefGoogle Scholar
  75. 75.
    Bjoro K, Gjerstad L, Bentdal O, et al. Topiramate and fulminant liver failure [letter]. Lancet 1998 Oct 3; 352(9134): 1119PubMedGoogle Scholar
  76. 76.
    Lasso-de-La-Vega MC, Zapater P, Such J, et al. Gaba-pentin-associated hepatotoxicity. Am J Gastroenterol 2001 Dec; 96(12): 3460–2PubMedCrossRefGoogle Scholar
  77. 77.
    Richardson CE, Williams DW, Kingham JG. Gabapentin induced cholestasis. BMJ 2002 Sep 21; 325(7365): 635PubMedCrossRefGoogle Scholar
  78. 78.
    Brockmann K, Hanefeld F. Progressive elevation of liver enzymes in a child treated with sulthiame. Neuropediatrics 2001 Jun; 32(3): 165–6PubMedCrossRefGoogle Scholar
  79. 79.
    Hubble JP, Koller WC, Cutler NR, et al. Pramipexole in patients with early Parkinson’s disease. Clin Neuropharmacol 1995 Aug; 18(4): 338–47PubMedCrossRefGoogle Scholar
  80. 80.
    Maxwell JD, Carrella M, Parkes JD, et al. Plasma disappearance and cerebral effects of chlorpromazine in cirrhosis. Clin Sci 1972 Aug; 43(2): 143–51PubMedGoogle Scholar
  81. 81.
    Dincsoy HP, Saelinger DA. Haloperidol-induced chronic cholestatic liver disease. Gastroenterology 1982 Sep; 83(3): 694–700PubMedGoogle Scholar
  82. 82.
    Ozcanli T, Erdogan A, Ozdemir S, et al. Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity. Prog Neuropsychopharmacol Biol Psychiatry 2006 Aug 30; 30(6): 1163–6PubMedCrossRefGoogle Scholar
  83. 83.
    El Hajj I, Sharara AI, Rockey DC. Subfulminant liver failure associated with quetiapine. Eur J Gastroenterol Hepatol 2004 Nov; 16(12): 1415–8PubMedCrossRefGoogle Scholar
  84. 84.
    Cohen LS, Cohen DE. Lithium-induced hyperbilir-ubinemia in an adolescent. J Clin Psychopharmacol 1991 Aug; 11(4): 274–5PubMedCrossRefGoogle Scholar
  85. 85.
    Hazelwood RE. Ascites: a side effect of lithium [letter]? Am J Psychiatry 1981 Feb; 138(2): 257PubMedGoogle Scholar
  86. 86.
    Krebs S, Dormann H, Muth-Selbach U, et al. Risperidone-induced cholestatic hepatitis. Eur J Gastroenterol Hepatol 2001 Jan; 13(1): 67–9PubMedCrossRefGoogle Scholar
  87. 87.
    Morgan DD, Robinson JD, Mendenhall CL. Clinical pharmacokinetics of chlordiazepoxide in patients with alcoholic hepatitis. Eur J Clin Pharmacol 1981 Mar; 19(4): 279–85PubMedCrossRefGoogle Scholar
  88. 88.
    Karsenti D, Blanc P, Bacq Y, et al. Hepatotoxicity associated with zolpidem treatment. BMJ 1999 May 1; 318(7192): 1179PubMedCrossRefGoogle Scholar
  89. 89.
    van Vliet AC, Frenkel M, Wilson JH. Acute liver necrosis after treatment with opipramol. Ned Tijdschr Geneeskd 1977 Aug 20; 121(34): 1325–7PubMedGoogle Scholar
  90. 90.
    Cai Q, Benson MA, Talbot TJ, et al. Acute hepatitis due to fluoxetine therapy. Mayo Clin Proc 1999 Jul; 74(7): 692–4PubMedCrossRefGoogle Scholar
  91. 91.
    Lopez-Torres E, Lucena MI, Seoane J, et al. Hepatotoxicity related to citalopram. Am J Psychiatry 2004 May; 161(5): 923–4PubMedCrossRefGoogle Scholar
  92. 92.
    Green BH. Fluvoxamine and hepatic function. Br J Psychiatry 1988 Jul; 153: 130–1PubMedCrossRefGoogle Scholar
  93. 93.
    Timmings P, Lamont D. Intrahepatic cholestasis associated with moclobemide leading to death. Lancet 1996 Mar 16; 347(9003): 762–3PubMedCrossRefGoogle Scholar
  94. 94.
    Otani K, Kaneko S, Tasaki H, et al. Hepatic injury caused by mianserin. BMJ 1989 Aug 19; 299(6697): 519PubMedCrossRefGoogle Scholar
  95. 95.
    Hui CK, Yuen MF, Wong WM, et al. Mirtazapine-induced hepatotoxicity. J Clin Gastroenterol 2002 Sep; 35(3): 270–1PubMedCrossRefGoogle Scholar
  96. 96.
    Horsmans Y, De Clercq M, Sempoux C. Venlafaxine-associated hepatitis [letter]. Ann Intern Med 1999 Jun 1; 130(11): 944PubMedGoogle Scholar
  97. 97.
    Cardona X, Avila A, Castellanos P. Venlafaxine-associated hepatitis [letter]. Ann Intern Med 2000 Mar 7; 132(5): 417PubMedGoogle Scholar
  98. 98.
    Hu KQ, Tiyyagura L, Kanel G, et al. Acute hepatitis induced by bupropion. Dig Dis Sci 2000 Sep; 45(9): 1872–3PubMedCrossRefGoogle Scholar
  99. 99.
    Alvaro D, Onetti-Muda A, Moscatelli R, et al. Acute cholestatic hepatitis induced by bupropion prescribed as pharmacological support to stop smoking: a case report. Dig Liver Dis 2001 Nov; 33(8): 703–6PubMedCrossRefGoogle Scholar
  100. 100.
    Jones DE, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther 2007 Feb 15; 25(4): 471–6PubMedCrossRefGoogle Scholar
  101. 101.
    Alvin J, McHorse T, Hoyumpa A, et al. The effect of liver disease in man on the disposition of phenobarbital. J Pharmacol Exp Ther 1975 Jan; 192(1): 224–35PubMedGoogle Scholar
  102. 102.
    Pisani F, Perucca E, Primerano G, et al. Single-dose kinetics of primidone in acute viral hepatitis. Eur J Clin Pharmacol 1984; 27(4): 465–9PubMedCrossRefGoogle Scholar
  103. 103.
    Blaschke TF, Meffin PJ, Melmon KL, et al. Influence of acute viral hepatitis on phenytoin kinetics and protein binding. Clin Pharmacol Ther 1975 Jun; 17(6): 685–91PubMedGoogle Scholar
  104. 104.
    Pacifici GM, Viani A, Rizzo G, et al. Plasma protein binding of clonazepam in hepatic and renal insufficiency and after hemodialysis. Ther Drug Monit 1987 Dec; 9(4): 369–73PubMedCrossRefGoogle Scholar
  105. 105.
    Vasudevan AE, Goh KL, Bulgiba AM. Impairment of psychomotor responses after conscious sedation in cirrhotic patients undergoing therapeutic upper GI endoscopy. Am J Gastroenterol 2002 Jul; 97(7): 1717–21PubMedCrossRefGoogle Scholar
  106. 106.
    Klotz U, Rapp T, Muller WA. Disposition of valproic acid in patients with liver disease. Eur J Clin Pharmacol 1978 Mar 17; 13(1): 55–60PubMedCrossRefGoogle Scholar
  107. 107.
    Krahenbuhl S, Brandner S, Kleinle S, et al. Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. Liver 2000 Jul; 20(4): 346–8PubMedCrossRefGoogle Scholar
  108. 108.
    Marcellin P, de Bony F, Garret C, et al. Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol 2001 May; 51(5): 410–4PubMedCrossRefGoogle Scholar
  109. 109.
    Brockmoller J, Thomsen T, Wittstock M, et al. 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 2005 Jun; 77(6): 529–41PubMedCrossRefGoogle Scholar
  110. 110.
    Whiteman PD, Fowle AS, Hamilton MJ, et al. Pharmacokinetics and pharmacodynamics of procyclidine in man. Eur J Clin Pharmacol 1985; 28(1): 73–8PubMedCrossRefGoogle Scholar
  111. 111.
    Jorga KM, Kroodsma JM, Fotteler B, et al. Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites. Clin Pharmacol Ther 1998 Jun; 63(6): 646–54PubMedCrossRefGoogle Scholar
  112. 112.
    Read AE, Laidlaw J, McCarthy CF. Effects of chlorpromazine in patients with hepatic disease. Br Med J 1969 Aug 30; 3(5669): 497–9PubMedCrossRefGoogle Scholar
  113. 113.
    Hu OY, Tang HS, Sheeng TY, et al. Pharmacokinetics of promazine: I. Disposition in patients with acute viral hepatitis B. Biopharm Drug Dispos 1990 Oct; 11(7): 557–68PubMedCrossRefGoogle Scholar
  114. 114.
    Hu OY, Tang HS, Sheeng TY, et al. Pharmacokinetics of promazine in patients with hepatic cirrhosis: correlation with a novel galactose single point method. J Pharm Sci 1995 Jan; 84(1): 111–4PubMedCrossRefGoogle Scholar
  115. 115.
    Zhang WV, Ramzan I, Murray M. Impaired microsomal oxidation of the atypical antipsychotic agent clozapine in hepatic steatosis. J Pharmacol Exp Ther 2007 Aug; 322(2): 770–7PubMedCrossRefGoogle Scholar
  116. 116.
    Thyrum PT, Wong YW, Yeh C. Single-dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment. Prog Neuropsychopharmacol Biol Psychiatry 2000 May; 24(4): 521–33PubMedCrossRefGoogle Scholar
  117. 117.
    Snoeck E, Van Peer A, Sack M, et al. Influence of age, renal and liver impairment on the pharmacokinetics of risper-idone in man. Psychopharmacology (Berl) 1995 Dec; 122(3): 223–9CrossRefGoogle Scholar
  118. 118.
    Klotz U, Antonin KH, Brugel H, et al. Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease. Clin Pharmacol Ther 1977 Apr; 21(4): 430–6PubMedGoogle Scholar
  119. 119.
    Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975 Feb; 55(2): 347–59PubMedCrossRefGoogle Scholar
  120. 120.
    Andreasen PB, Hendel J, Greisen G, et al. Pharmacokinetics of diazepam in disordered liver function. Eur J Clin Pharmacol 1976 Jun 15; 10(2): 115–20PubMedCrossRefGoogle Scholar
  121. 121.
    Branch RA, Morgan MH, James J, et al. Intravenous administration of diazepam in patients with chronic liver disease. Gut 1976 Dec; 17(12): 975–83PubMedCrossRefGoogle Scholar
  122. 122.
    Bozkurt P, Kaya G, Suzer O, et al. Diazepam serum concentration-sedative effect relationship in patients with liver disease. Middle East J Anesthesiol 1996 Feb; 13(4): 405–13PubMedGoogle Scholar
  123. 123.
    Sellers EM, Greenblatt DJ, Giles HG, et al. Chlordiazepoxide and oxazepam disposition in cirrhosis. Clin Pharmacol Ther 1979 Aug; 26(2): 240–6PubMedGoogle Scholar
  124. 124.
    Roberts RK, Wilkinson GR, Branch RA, et al. Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide (librium). Gastroenterology 1978 Sep; 75(3): 479–85PubMedGoogle Scholar
  125. 125.
    Shull HJ, Wilkinson GR, Johnson R, et al. Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann Intern Med 1976 Apr; 84(4): 420–5PubMedGoogle Scholar
  126. 126.
    Kraus JW, Desmond PV, Marshall JP, et al. Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther 1978 Oct; 24(4): 411–9PubMedGoogle Scholar
  127. 127.
    Monjanel-Mouterde S, Antoni M, Bun H, et al. Pharmacokinetics of a single oral dose of clobazam in patients with liver disease. Pharmacol Toxicol 1994 Jun; 74(6): 345–50PubMedCrossRefGoogle Scholar
  128. 128.
    Juhl RP, Van Thiel DH, Dittert LW, et al. Alprazolam pharmacokinetics in alcoholic liver disease. J Clin Pharmacol 1984 Feb–Mar; 24(2-3): 113–9PubMedGoogle Scholar
  129. 129.
    Dalhoff K, Poulsen HE, Garred P, et al. Buspirone pharmacokinetics in patients with cirrhosis. Br J Clin Pharmacol 1987 Oct; 24(4): 547–50PubMedCrossRefGoogle Scholar
  130. 130.
    Barbhaiya RH, Shukla UA, Pfeffer M, et al. Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses. Eur J Clin Pharmacol 1994; 46(1): 41–7PubMedCrossRefGoogle Scholar
  131. 131.
    Jochemsen R, Van Beusekom BR, Spoelstra P, et al. Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam. Br J Clin Pharmacol 1983 Mar; 15(3): 295–302PubMedCrossRefGoogle Scholar
  132. 132.
    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(6): 643–51PubMedCrossRefGoogle Scholar
  133. 133.
    Bakti G, Fisch HU, Karlaganis G, et al. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology 1987 Jul–Aug; 7(4): 629–38PubMedCrossRefGoogle Scholar
  134. 134.
    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 Aug; 27(8): 555–60PubMedGoogle Scholar
  135. 135.
    Robin DW, Lee M, Hasan SS, et al. Triazolam in cirrhosis: pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993 Dec; 54(6): 630–7PubMedCrossRefGoogle Scholar
  136. 136.
    Hildebrand M, Hellstern A, Humpel M, et al. Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers. Eur J Drug Metab Pharmacokinet 1990 Jan–Mar; 15(1): 19–26PubMedCrossRefGoogle Scholar
  137. 137.
    Ghabrial H, Desmond PV, Watson KJ, et al. The effects of age and chronic liver disease on the elimination of temazepam. Eur J Clin Pharmacol 1986; 30(1): 93–7PubMedCrossRefGoogle Scholar
  138. 138.
    Ochs HR, Greenblatt DJ, Verburg-Ochs B, et al. Temazepam clearance unaltered in cirrhosis. Am J Gastroenterol 1986 Jan; 81(1): 80–4PubMedGoogle Scholar
  139. 139.
    Trouvin JH, Farinotti R, Haberer JP, et al. Pharmacokinetics of midazolam in anaesthetized cirrhotic patients. Br J Anaesth 1988 Jun; 60(7): 762–7PubMedCrossRefGoogle Scholar
  140. 140.
    MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986 Feb; 27(2): 190–5PubMedCrossRefGoogle Scholar
  141. 141.
    Pentikainen PJ, Valisalmi 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 Mar; 29(3): 272–7PubMedGoogle Scholar
  142. 142.
    Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology 2001 Dec; 34(6): 1103–8PubMedCrossRefGoogle Scholar
  143. 143.
    Parker G, Roberts CJ. Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease. Br J Clin Pharmacol 1983 Sep; 16(3): 259–65PubMedCrossRefGoogle Scholar
  144. 144.
    Meredith CG, Christian Jr CD, et al. Diphenhydramine disposition in chronic liver disease. Clin Pharmacol Ther 1984 Apr; 35(4): 474–9PubMedCrossRefGoogle Scholar
  145. 145.
    Pentikainen PJ, Neuvonen PJ, Jostell KG. Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver. Eur J Clin Pharmacol 1980 Apr; 17(4): 275–84PubMedCrossRefGoogle Scholar
  146. 146.
    Centerholt C, Ekblom M, Odergren T, et al. Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole. Eur J Clin Pharmacol 2003 Jun; 59(2): 117–22PubMedGoogle Scholar
  147. 147.
    Hrdina PD, Lapierre YD, Koranyi EK. Altered amitriptyline kinetics in a depressed patient with porto-caval anastomosis. Can J Psychiatry 1985 Mar; 30(2): 111–3PubMedGoogle Scholar
  148. 148.
    Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1986 Dec; 32(6): 481–508PubMedCrossRefGoogle Scholar
  149. 149.
    Schenker S, Bergstrom RF, Wolen RL, et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988 Sep; 44(3): 353–9PubMedCrossRefGoogle Scholar
  150. 150.
    Joffe P, Larsen FS, Pedersen V, et al. Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects. Eur J Clin Pharmacol 1998 May; 54(3): 237–42PubMedCrossRefGoogle Scholar
  151. 151.
    Dalhoff K, Almdal TP, Bjerrum K, et al. Pharmacokinetics of paroxetine in patients with cirrhosis. Eur J Clin Pharmacol 1991; 41(4): 351–4PubMedCrossRefGoogle Scholar
  152. 152.
    Demolis JL, Angebaud P, Grange JD, et al. Influence of liver cirrhosis on sertraline pharmacokinetics. Br J Clin Pharmacol 1996 Sep; 42(3): 394–7PubMedCrossRefGoogle Scholar
  153. 153.
    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 Feb; 24(2): 177–82PubMedCrossRefGoogle Scholar
  154. 154.
    Areberg J, Christophersen JS, Poulsen MN, et al. The pharmacokinetics of escitalopram in patients with hepatic impairment. AAPS J 2006; 8(1): E14–9PubMedCrossRefGoogle Scholar
  155. 155.
    Stoeckel K, Pfefen JP, Mayersohn M, et al. Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function. Acta Psychiatr Scand Suppl 1990; 360: 94–7PubMedCrossRefGoogle Scholar
  156. 156.
    Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000 Jun; 38(6): 461–74PubMedCrossRefGoogle Scholar
  157. 157.
    Tran A, Laneury J, Duchêne P, et al. Pharmacokinetics of reboxetine in volunteers with hepatic impairment. Clin Drug Invest 2000; 19(6): 473–7CrossRefGoogle Scholar
  158. 158.
    DeVane CL, Laizure SC, Stewart JT, et al. Disposition of bupropion in healthy volunteers and subjects with alcoholic liver disease. J Clin Psychopharmacol 1990 Oct; 10(5): 328–32Google Scholar
  159. 159.
    Zhao Q, Iyer GR, Verhaeghe T, et al. Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers. J Clin Pharmacol 2002 Apr; 42(4): 428–36PubMedCrossRefGoogle Scholar
  160. 160.
    Reyes JF, Vargas R, Kumar D, et al. Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients. Br J Clin Pharmacol 2004 Nov; 58 Suppl. 1: 9–17PubMedCrossRefGoogle Scholar
  161. 161.
    Tiseo PJ, Vargas R, Perdomo CA, et al. An evaluation of the pharmacokinetics of donepezil HCl in patients with impaired hepatic function. Br J Clin Pharmacol 1998 Nov; 46 Suppl. 1: 51–5PubMedCrossRefGoogle Scholar
  162. 162.
    Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973 Aug; 60(8): 646–9PubMedCrossRefGoogle Scholar
  163. 163.
    Wilkinson GR. Clearance approaches in pharmacology. Pharmacol Rev 1987 Mar; 39(1): 1–47PubMedGoogle Scholar
  164. 164.
    Ito K, Houston JB. Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes. Pharm Res 2004 May; 21(5): 785–92PubMedCrossRefGoogle Scholar
  165. 165.
    Frye RF, Zgheib NK, Matzke GR, et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 2006 Sep; 80(3): 235–45PubMedCrossRefGoogle Scholar
  166. 166.
    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 Jan; 21(1): 120–8PubMedGoogle Scholar
  167. 167.
    Branch RA. Drugs in liver disease. Clin Pharmacol Ther 1998 Oct; 64(4): 462–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Chantal Schlatter
    • 1
  • Sabin S. Egger
    • 1
  • Lydia Tchambaz
    • 1
  • Stephan Krähenbühl
    • 1
  1. 1.Division of Clinical Pharmacology & ToxicologyUniversity HospitalBaselSwitzerland

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