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Carbamazepine-Provoked Hepatotoxicity and Possible Aetiopathological Role of Glutathione in the Events

Retrospective Review of Old Data and Call for New Investigation

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Adverse Drug Reactions and Toxicological Reviews

Abstract

The antiepileptic drug (AED) carbamazepine is widely used in the treatment of different kinds of seizures as well as affective and behavioural disorders. This paper presents an epidemiological study of carbamazepine-induced hepatic injuries and death, and describes the possible mechanisms of its toxicity. A retrospective analysis of clinical data revealed that the likelihood of hepatic death was comparatively higher in children, particularly when they were receiving medication with multiple AEDs, whereas reversible hepatic injuries were more likely to be seen in elderly patients. As suggested in this paper, the development of carbamazepine hepatotoxicity is rare, and unpredictable with the present state of knowledge, but it is somehow related to disturbance of glutathione metabolism, although data in this regard are imperfect. There appear to be two types of carbamazepine-initiated idiosyncratic liver injury, hypersensitivity and toxin-induced. It is feasible that both are due to the accumulation of toxic metabolite(s), and arene oxides may probably be considered as damaging derivatives of carbamazepine metabolism. Despite the lack of clear-cut underlying clinical and experimental findings in those patients in whom an inherited weakness of drug eliminating capacity is present, those conditions that may deteriorate glutathione balance, may increase the possibility of the emergence of toxic events during carbamazepine therapy. Finally, some recommendations for carbamazepine therapy are presented.

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References

  1. Sillanpaa M. Carbamazepine: pharmacology and clinical uses. Acta Neurol Scand 1981; 64 Suppl. 88: 1–202

    Google Scholar 

  2. Levy RH, Pitlick WD, Troupin AS et al. Pharmacokinetics of carbamazepine in normal man. Clin Pharmacol Ther 1975; 17: 657–68

    PubMed  CAS  Google Scholar 

  3. Penovich PE, Morgan JP. Carbamazepine: a review. Drug Ther 1976; 6: 187–93

    Google Scholar 

  4. Post RM, Uhde TW, Roy-Byrne PP et al. Antidepressant effects of carbamazepine. Am J Psychiatry 1986; 143: 29–34

    PubMed  CAS  Google Scholar 

  5. Ballanger JC. The clinical use of carbamazepine in affective disorders. J Clin Psychiatry 1988; 49 Suppl.: 13–9

    Google Scholar 

  6. Frigerio A, Fanelli R, Passerini G et al. Mass spectrometric characterization of carbamazepine-10, 11-epoxide, a carbamazepine metabolite isolated from human urine. J Pharm Sci 1972; 61: 1144–7

    Article  PubMed  CAS  Google Scholar 

  7. Lertratanangkoon K, Horning MG. Metabolism of carbamazepine. Drug Metab Dispos 1982; 10: 1–10

    PubMed  CAS  Google Scholar 

  8. Dreifuss FE, Langer DH. Hepatic considerations in the use of antiepileptic drugs. Epilepsia 1987; 28 Suppl. 2: 23–9

    Article  Google Scholar 

  9. Gram L, Bentsten KD. Hepatic toxicity of antiepileptic drugs: a review. Acta Neurol Scand 1983; 68 Suppl. 97: 81–90

    Article  Google Scholar 

  10. Dreifuss FE, Santilli N, Langer DH et al. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987; 37: 379–85

    Article  PubMed  CAS  Google Scholar 

  11. Dreifuss FE, Langer DH, Moline KA et al. Valproic acid hepatic fatalities: II. US experience since 1984. Neurology 1989; 39: 201–7

    Article  PubMed  CAS  Google Scholar 

  12. Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10, 11-epoxide. Clin Pharmacokinet 1986; 11: 177–98

    Article  PubMed  CAS  Google Scholar 

  13. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. Clin Pharmacokinet 1996; 31: 198–214

    Article  PubMed  CAS  Google Scholar 

  14. Björquist SE, Isohanni M, Makela R, et al. Ambulant treatment of alcohol withdrawal symptoms with carbamazepine: a formal multicentre double-bind comparison with placebo. Acta Psychiatr Scand 1976; 53: 333–42

    Article  Google Scholar 

  15. Sillanpaa M, Sonck T. Finnish experienceswith carbamazepine (Tegretolo) in the treatment of acute withdrawal symptoms in alcoholics. J Int Med Res 1979; 7: 168–73

    PubMed  CAS  Google Scholar 

  16. Gehlen W, Fröscher W, Bron B. Nebenwirkungen antiepileptischer medikamente. Internist Prax 1978; 18: 333–9

    Google Scholar 

  17. Davies-Jones, GAB. Carbamazepine. In: Dukes MNG, editor. Meyler’s side effects of drugs. Amsterdam: Elsevier, 1988: 127–8

    Google Scholar 

  18. Askmark H, Wiholm B. Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system. Acta Neurol Scand 1990; 81: 131–40

    Article  PubMed  CAS  Google Scholar 

  19. Harden CL. Therapeutic safetymonitoring: what to look for and when to look for it. Epilepsia 2000; 41 Suppl. 8: 37–44

    Article  Google Scholar 

  20. Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. N Engl J Med 1992; 327: 765–71

    Article  PubMed  CAS  Google Scholar 

  21. Kalvainen R, Aikia M, Saukkonen AM, et al. Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy. Arch Neurol 1995; 52: 989–96

    Article  Google Scholar 

  22. Plaa G. Acute toxicity of antiepileptic drugs. Epilepsia 1975; 16: 183–91

    Article  PubMed  CAS  Google Scholar 

  23. Madden S, Maggs JL, Park BK. Activation of carbamazepine in the rat in vivo. Evidence for the formation of reactive arene oxide(s). Drug Metab Dispos 1996; 24: 469–79

    PubMed  CAS  Google Scholar 

  24. Csetényi J, Baker KM, Frigerio A, et al. Iminostilbene: a metabolite of carbamazepine isolated fromrat urine. J Pharm Pharmacol 1973; 25: 340–1

    Article  PubMed  Google Scholar 

  25. deBethizy JD, Hayes JR. Metabolism: a determinant of toxicity. In: Hayes AW, editor. Principles and methods of toxicology. 2nd ed. New York: Raven Press, 1988: 29–66

    Google Scholar 

  26. Eichelbaum M, Tomson T, Tybring G, et al. Carbamazepine metabolism in man/Induction and pharmacogenetic aspects. Clin Pharmacokinet 1985; 10: 80–90

    Article  PubMed  CAS  Google Scholar 

  27. Rane A, Höjer B, Wilson JT. Kinetics of carbamazepine and its 10, 11-epoxide metabolite in children. Clin Pharmacol Ther 1976; 19: 276–83

    PubMed  CAS  Google Scholar 

  28. Jung R, Bentley P, Oesch F. Influence of carbamazepine 10, 11-epoxide on drug metabolizing enzymes. Biochem Pharmacol 1980; 29: 1109–12

    Article  PubMed  CAS  Google Scholar 

  29. Tybring G, von Bahr C, Bertilsson L, et al. Metabolism of carbamazepine and its epoxide metabolite in human and rat liver in vitro. Drug Metab Dispos 1981; 9: 561–4

    PubMed  CAS  Google Scholar 

  30. Bernus I, Dickinson RG, Hooper WD, et al. Early stage autoinduction of carbamazepine metabolism in humans. Eur J Clin Pharmacol 1994; 47: 355–60

    Article  PubMed  CAS  Google Scholar 

  31. Kerr BL, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10, 11-epoxide formation. Biochem Pharmacol 1994; 47: 1969–79

    Article  PubMed  CAS  Google Scholar 

  32. Bertilsson L, Tomson T, Tybring G. Pharmacokinetics: timedependent changes — autoinduction of carbamazepine epoxidation. J Clin Pharmacol 1986; 26: 459–62

    PubMed  CAS  Google Scholar 

  33. Gonzalez FJ. The molecular biology of cytochrome P450s. Pharmacol Rev 1989; 40: 244–88

    Google Scholar 

  34. Pynnönen S, Sillanpaa M, Frey H, et al. Carbamazepine and its 10, 11-epoxide in children and adults with epilepsy. Eur J Clin Pharmacol 1977; 11: 129–33

    Article  PubMed  Google Scholar 

  35. Lanchote VL, Bonato PS, Campos GM, et al. Factors influencing plasma concentrations of carbamazepine and carbamazepine 10, 11-epoxide in epileptic children and adults. Ther Drug Monit 1995; 17: 47–52

    Article  PubMed  CAS  Google Scholar 

  36. Johnson CM, Thummel KE, Kroetz DL, et al. Metabolism of CBZ by cytochrome P450 isoforms 3A4, 2C8 and 1A2. Pharm Res 1992; 9 Suppl.: s301

    Google Scholar 

  37. Pirmohamed M, Kitteringham NR, Guenther TM, et al. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol 1992; 43: 1675–82

    Article  PubMed  CAS  Google Scholar 

  38. Bazire S. Psychotropic drug directory. Organon: Mark Allen Publishing Ltd, 2000

    Google Scholar 

  39. Wu C, Uetrecht JP. Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate. J Pharm Exp Ther 1999; 288: 51–6

    Google Scholar 

  40. Furst SM, Uetrecht JP. Carbamazepine metabolism to a reactive intermediate by myeloperoxidase system of activated neutrophils. Biochem Pharmacol 1993; 45: 1267–75

    Article  PubMed  CAS  Google Scholar 

  41. Runci FM, Micheli L, Fiaschi AI, et al. Valproic acid and carbamazepine dramatically decrease the glutathione cerebral levels. Pharmacol Res 1990; 22 Suppl. 2: 437

    Article  Google Scholar 

  42. Attaguile G, Caruso A, Cutuli VMC, et al. Influence of sodium valproate and carbamazepine on GSH levels in rat cerebral cortex. Drugs Exp Clin Res 1992; 18: 465–7

    PubMed  CAS  Google Scholar 

  43. Yesilaltay AK, Ersoy Ö, Omurtag GZ, et al. Effects of carbamazepine on hepatic glutathione level in rats and determination of carbamazepine and its epoxide metabolite in plasma by HPLC. Drug Metabol Drug Interact 1988; 14: 251–8

    Article  Google Scholar 

  44. Kalapos MP, Garzó T, Antoni F, et al. Effect of methylglyoxal on glucose formation, drug oxidation and glutathione content in isolated murine hepatocytes. Biochim Biophys Acta 1991; 109: 284–90

    Article  Google Scholar 

  45. Smith CV, Jones DP, Guenthner TM, et al. Compartmentation of glutathione: implications for the study of toxicity and disease. Toxicol Appl Pharmacol 1996; 140: 1–12

    Article  PubMed  CAS  Google Scholar 

  46. Lillebridge JH, Amore BM, Slattery JT, et al. Protein-reactive metabolites of carbamazepine in mouse liver microsomes. Drug Metab Dispos 1996; 24: 509–14

    Google Scholar 

  47. Regnaud L, Sirois G, Chakrabarti S. Effect of four-day treatment with carbamazepine at different dose levels on microsomal enzyme induction, drug metabolism and drug toxicity. Pharmacol Toxicol 1988; 62: 3–6

    Article  PubMed  CAS  Google Scholar 

  48. Meister A. Glutathione metabolism and its selective modification. J Biol Chem 1988; 263: 17205–8

    PubMed  CAS  Google Scholar 

  49. Yüksel A, Cengiz M, Seven M, et al. Erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serumlipid peroxidation in epileptic children with valproate and carbamazepine monotherapy. J Basic Clin Physiol Pharmacol 2000; 11: 73–81

    Article  PubMed  Google Scholar 

  50. Cengiz M, Yüksel A, Seven M. The effects of carbamazepine and valproic acid on the erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children. Pharmacol Res 2000; 41: 423–5

    Article  PubMed  CAS  Google Scholar 

  51. Kürekci AE, Alpay F, Tanindi S, et al. Plasma trace element, plasma glutathione peroxidase, and superoxide dismutase levels in epileptic children receiving antiepileptic drug therapy. Epilepsia 1995; 36: 600–4

    Article  PubMed  Google Scholar 

  52. Liu CS, Wu HM, Kao SH, et al. Serum trace elements, glutathione, copper/zinc superoxide dismutase, and lipid peroxidation ion epileptic patients with phenytoin or carbamazepine monotherapy. Clin Neuropharm 1998; 21: 62–4

    CAS  Google Scholar 

  53. Ono H, Sakamoto A, Sakura N. Plasma total glutathione concentrations in epileptic patients taking anticonvulsants. Clin Chim Acta 2000; 298: 135–43

    Article  PubMed  CAS  Google Scholar 

  54. Gerson WT, Fine DG, Spielberg SP, et al. Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro. Blood 1983; 61: 889–93

    PubMed  CAS  Google Scholar 

  55. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. J Clin Invest 1988; 82: 1826–32

    Article  PubMed  CAS  Google Scholar 

  56. Pirmohamed M, Graham A, Roberts P, et al. Carbamazepine-hypersensitivity: assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbamazepine. Br J Clin Pharmacol 1991; 32: 741–9

    Article  PubMed  CAS  Google Scholar 

  57. Spielberg SP. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed Proc 1984; 43: 2308–213

    PubMed  CAS  Google Scholar 

  58. Ussery XT, Henar EL, Black DD et al. Acute liver injury after protracted seizures in children. J Pediatr Gastroenterol Nutr 1989; 9: 421–5

    Article  PubMed  CAS  Google Scholar 

  59. Coombes BW. Stevens-Johnson syndrome associated with carbamazepine (’Tegretol’). Med J Aust 1965; 1: 895–6

    Google Scholar 

  60. Ramsay ID. Carbamazepine-induced jaundice [letter]. BMJ 1967; 4: 155

    Article  PubMed  CAS  Google Scholar 

  61. Livingstone S, Villamater C, Sakata Y, et al. Use of carbamazepine in epilepsy. JAMA 1967; 200: 116–20

    Google Scholar 

  62. Dold U, Reichenmiller HE. Akute Leberschadigung beim menschen durch gleichzeitge gabe von isonikotinsaure-hydrazid und epileptika. Med Welt 1969; 1: 48–54

    PubMed  CAS  Google Scholar 

  63. Marotta JT. A long term study in trigeminal neuralgia. Headache 1969; 9: 83–7

    Article  PubMed  CAS  Google Scholar 

  64. Levander HG. Granulomatous hepatitis in a patient receiving carbamazepine. Acta Med Scand 1980; 208: 333–5

    Article  PubMed  CAS  Google Scholar 

  65. Levy M, Goodman MW, Van Dyne BJ, et al. Granulomatous hepatitis secondary to carbamazepine. Ann Intern Med 1981; 95: 64–5

    PubMed  CAS  Google Scholar 

  66. Mitchell MC, Boitnott JK, Arregui A, et al. Granulomatous hepatitis associated with carbamazepine therapy. Am J Med 1981; 71: 733–5

    Article  PubMed  CAS  Google Scholar 

  67. Soffer EE, Taylor RJ, Bertram PD, et al. Carbamazepine-induced liver injury}. South Med J 1983; 76: 681–3

    Article  PubMed  CAS  Google Scholar 

  68. Ponte CD. Carbamazepine-induced thrombocytopenia, rash, and hepatic dysfunction. Drug Intell Clin Pharm 1983; 17: 642–4

    PubMed  CAS  Google Scholar 

  69. Davion T, Capron JP, Andrejak M, et al. Hépatite aigue due á la carbamazepine (Tégrétol®). Gastroenterol Clin Biol 1984; 8: 52–6

    PubMed  CAS  Google Scholar 

  70. de Swert LF, Ceuppens JL, Teuwen D, et al. Acute interstitial pneumonitis and carbamazepine therapy. Acta Paediatr Scand 1984; 73: 285–8

    Article  PubMed  Google Scholar 

  71. Galeone D, Lamontanara G, Torelli D. Acute hepatitis in a patient treated with carbamazepine. J Neurol 1985; 232: 301–3

    Article  PubMed  CAS  Google Scholar 

  72. Swinburn BA, Croxson MS, Miller MV, et al. Carbamazepine induced granulomatous hepatitis [abstract]. N Z Med J 1986; 12: 167

    Google Scholar 

  73. Horowitz S, Patwardhan R, Marcus E. Hepatotoxic reactions associated with carbamazepine therapy. Epilepsia 1988; 29: 149–54

    Article  PubMed  CAS  Google Scholar 

  74. Hegbrant J, Kurkus J, Öquist B. Carbamazepine-related acute renal failure. Neurology 1993; 43: 446–7

    Article  PubMed  CAS  Google Scholar 

  75. Kaufman KR. Carbamazepine, hepatotoxicity, organic solvents, and paints. Seizure 1999; 8: 250–2

    Article  PubMed  CAS  Google Scholar 

  76. Fellows WR. A case of aplastic anemia and pancytopenia with Tegretol therapy. Headache 1969; 9: 91–3

    Google Scholar 

  77. Zucker P, Daum F, Cohen MI. Fatal carbamazepine hepatitis. J Pediatr 1977; 91: 667–8

    Article  PubMed  CAS  Google Scholar 

  78. Hopen G, Nesthus I, Laerum OD. Fatal carbamazepine-associated hepatitis. Acta Med Scand 1981; 210: 333–5

    Article  PubMed  CAS  Google Scholar 

  79. Smith DW, Cullity GJ, Silberstein EP. Fatal hepatic necrosis associated with multiple anticonvulsant therapy. Aust N Z J Med 1988; 18: 575–81

    Article  PubMed  CAS  Google Scholar 

  80. Decell MK, Gordon JB, Silver K, et al. Fulminant hepatic failure associated with status epilepticus in children: three cases and a review of potential mechanisms. Intensive Care Med 1994; 20: 375–8

    Article  PubMed  CAS  Google Scholar 

  81. Zimmerman H. Drug-induced liver disease. Drugs 1978; 16: 25–45

    Article  PubMed  CAS  Google Scholar 

  82. Spillane JD. The treatment of trigeminal neuralgia. Practioner 1964; 192: 71–7

    CAS  Google Scholar 

  83. Killian JM, Fromm GH. Carbamazepine in the treatment of neuralgia. Arch Neurol 1968; 19: 129–36

    Article  PubMed  CAS  Google Scholar 

  84. Nebert DW, Levitt RC, Jensen NM, et al. Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus. Arch Toxicol 1977; 39: 109–32

    Article  PubMed  CAS  Google Scholar 

  85. Donaldson GWK, Graham JG. Aplastic anaemia following the administration of Tegretol. Br J Clin Pract 1965; 19: 699–702

    PubMed  CAS  Google Scholar 

  86. Bird CAK, Griffin BP, Miklaszewska JM, et al. Tegretol (carbamazepine): a controlled trial of a new anti-convulsant. Br J Psychiatry 1966; 112: 737–42

    Article  Google Scholar 

  87. ADRAC Commettee. ADRAC report for 1977. Med J Aust 1978; 2 Suppl.: s1–2

    Google Scholar 

  88. Specht U, May TW, Rohde M, et al. Cerebellar atrophy decreases the threshold of carbamazepine toxicity in patients with chronic focal epilepsy. Arch Neurol 1997; 54: 427–31

    Article  PubMed  CAS  Google Scholar 

  89. Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother 1999; 33: 790–2

    Article  PubMed  CAS  Google Scholar 

  90. Mateu-de Antonio J, Grau S, Gimeno-Bayon JL, et al. Ritonavir-induced carbamazepine toxicity. Ann Pharmacother 2001; 35: 125–6

    Article  Google Scholar 

  91. Sullivan JB, Rumack BH, Peterson RG. Acute carbamazepine toxicity resulting from overdose. Neurology 1981; 31: 621–4

    Article  PubMed  Google Scholar 

  92. Sethna M, Solomon G, Cederbaum J, et al. Successful treatment of massive carbamazepine overdose. Epilpesia 1989; 30: 71–3

    Article  CAS  Google Scholar 

  93. Queen JR. A 41-year-old woman with confusion and unsteady gait. Clev Clin J Med 2000; 67: 505–10

    CAS  Google Scholar 

  94. Durelli L, Massazza U, Cavallo R. Carbamazepine toxicity and poisoning. Med Toxicol Adverse Drug Exp 1989; 4: 95–107

    PubMed  CAS  Google Scholar 

  95. Albani F, Riva R, Baruzzi A. Carbamazepine clinical pharmacology: a review. Pharmacopsychiatry 1995; 28: 235–44

    Article  PubMed  CAS  Google Scholar 

  96. Boldy DAR, Heath A, Ruddock S, et al. Activated charcoal for carbamazepine poisoning [letter]. Lancet 1987; I: 1027

    Article  Google Scholar 

  97. Kalapos MP, Debreczeni J, Széll K, et al. Does carbamazepineepoxide conjugate with glutathione? Drug Metab Drug Interact 2000; 16: 229–35

    Article  CAS  Google Scholar 

  98. Glatt HR, Oesch F, Frigerio A, et al. Epoxides metabolically produced from some known carcinogens and from some clinically used drugs: I. differences in mutagenicity. Int J Cancer 1975; 16: 787–97

    Article  PubMed  CAS  Google Scholar 

  99. Bourgeois BFD, Wad N. Individual and combined antiepileptic and neurotoxic activity of carbamazepine and carbamazepine-10,11-epoxide in mice. J Pharmacol Exp Ther 1984; 231: 411–5

    PubMed  CAS  Google Scholar 

  100. Morris JC, Dodson WE, Hatlelid JM, et al. Phenytoin and carbamazepine, alone and in combination. Neurology 1987; 37: 1111–8

    Article  PubMed  CAS  Google Scholar 

  101. Gennings C, Sofia RD, Carchman RA, et al. Analysis of anticonvulsant and neurotoxic responses to combination therapy with carbamazepine, felbamate, and phenytoin by response-surface modeling. Arzneimittel Forschung 1995; 45: 739–48

    PubMed  CAS  Google Scholar 

  102. Stenger EG, Roulet FC. Zur Toxikologie des antiepilepticum tegretol. Med Exper 1964; 11: 191–201

    CAS  Google Scholar 

  103. Black M. Acetaminophen hepatotoxicity. Annu Rev Med 1984; 35: 577–93

    Article  PubMed  CAS  Google Scholar 

  104. Owens CWI, Parker NE, Nunn PP, et al. Agranulocytosis associated with carbamazepine, and positive reaction with antilymphoid leukemia antiserum during recovery. Postgrad Med J 1980; 56: 665–8

    Article  PubMed  CAS  Google Scholar 

  105. Gonzalez FJ, Idle JR. Pharmacogenetic phenotyping and genotyping. Clin Pharmacokinet 1994; 26: 59–70

    Article  PubMed  CAS  Google Scholar 

  106. Larrey D, Pageaux GP. Genetic disposition to drug-induced hepatotoxicity. J Hepatol 1997; 26 Suppl. 2: 12–21

    Article  PubMed  CAS  Google Scholar 

  107. Lindhout D, Höppener RJEA, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984; 25: 77–83

    Article  PubMed  CAS  Google Scholar 

  108. Dutton GJ. Developmental aspects of drug conjugation, with special reference to glucuronidation. Ann Rev Pharmacol Toxicol 1978; 18: 17–35

    Article  CAS  Google Scholar 

  109. Mandl J, Bánhegyi G, Kalapos MP, et al. Increased oxidation and decreased conjugation of drugs in the liver caused by starvation: altered metabolism of certain aromatic compounds and acetone. Chem Biol Interact 1995; 96: 87–101

    Article  PubMed  CAS  Google Scholar 

  110. Kidd PM. Glutathione: systemic protectant against oxidative and free radical damage. Altern Med Rev 1997; 2: 155–76

    Google Scholar 

  111. DeMaster EG, Nagasawa HT. Disulfiram-induced acetonemia in the rat and man. Res Commun Chem Pathol Pharmacol 1977; 18: 361–4

    CAS  Google Scholar 

  112. Stipanuk MH, Coloso RM, Garcia RAG, et al. Cysteine concentration regulates cysteine metabolism to glutathione, sulfate and taurine in rat hepatocytes. J Nutr 1992; 122: 420–7

    PubMed  CAS  Google Scholar 

  113. Billings R. Mechanisms of catechol formation from aromatic compounds in isolated rat hepatocytes. Drug Metab Dispos 1985; 13: 287–9

    PubMed  CAS  Google Scholar 

  114. Kappus H. Overview of enzyme systems involved in bioreduction of drugs and redox cycling. Biochem Pharmacol 1986; 35: 1–6

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Thanks are due to Etelka Imre, BSc (Theoretical Biology Research Group, Budapest, Hungary), John R. Queen, MD (The Cleveland Clinic Foundation, Cleveland, USA) and John E. Piletz, PhD (University of Mississippi, Jackson, USA) for their help in the preparation of the paper and the collection of literature. The preparation of this paper was made possible by the Theoretical Biology Research Group, Budapest, Hungary. The material of the paper was presented in part as a poster in the CINP Hungarian Regional Congress jointly with the 4th Hungarian Neuropsychopharmacologic Congress, Budapest, September 2001.

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    Miklós Péter Kalapos

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Kalapos, M.P. Carbamazepine-Provoked Hepatotoxicity and Possible Aetiopathological Role of Glutathione in the Events. Adv Drug React Toxicol Rev 21, 123–141 (2002). https://doi.org/10.1007/BF03256188

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