Clinical Pharmacokinetics

, Volume 34, Issue 3, pp 219–226

Drug Acetylation in Liver Disease

  • Micha Levy
  • Yoseph Caraco
  • Gerd Geisslinger
Review Article Special Populations


N-Acetylation is a phase II conjugation reaction mediated in humans by the polymorphic N-acetyltransferase 2 (NAT2) and N-acetyltransferase 1 (NAT1). Acetylation of some drugs may be modestly decreased in patients with chronic liver disease, whereas acute liver injury has no effect on drug acetylation. For NAT2 substrates, the impairment in acetylation capacity seems to be phenotype-specific, with a more prominent effect being exerted in rapid than slow acetylators. Thus, in the presence of significant hepatic dysfunction, the activity of NAT2 may not exhibit its usual bimodal distribution, and hence phenotypic assignment may not be reliable. Furthermore, it remains to be evaluated whether the precautions advised for slow acetylators when treated with drugs metabolised by NAT2 apply to all patients (regardless of phenotype) with liver cirrhosis.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weber WW, Hein DW. N-acetylation pharmacogenetics. Pharmacol Rev. 1985; 37: 25–79.PubMedGoogle Scholar
  2. 2.
    Cribb AE, Nakamura H, Grant DM, et al. Role of polymorphic and monomorphic human arylamine N-acetyltransferases in determining sulfamethoxazole metabolism. Biochem Pharmacol. 1993; 45: 1277–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Vatsis KP, Weber WW, Bell DA, et al. Nomenclature for N-acetyltransferase. Pharmacogenetics. 1995; 5: 1–17.PubMedCrossRefGoogle Scholar
  4. 4.
    Grant DM, Houghes NC, Janezic SA, et al. Human acetyl-transferase polymorphisms. Mutat Res 1997; 376; 61–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Perry Jr HM, Tan EM, Carmody S, et al. Relationship of acetyl transferase activity to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine. J Lab Clin Med. 1970; 76: 114–25.PubMedGoogle Scholar
  6. 6.
    Lunde PKM, Frislid K, Haustein V. Disease and acetylation polymorphism. Clin Pharmacokinet. 1977; 2: 182–97.PubMedCrossRefGoogle Scholar
  7. 7.
    Woosley RL, Drayer DE, Reidenberg MM, et al. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N Engl J Med. 1978; 298: 1157–9.PubMedCrossRefGoogle Scholar
  8. 8.
    O’Neil WM, Gilfix BM, DiGirolamo A, et al. N-Acetylation among HIV-positive patients and patients with AIDS: when is fast, fast and slow, slow? Clin Pharmacol Ther. 1997; 62: 261–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Shear NA, Spielberg SP, Grant DM, et al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med. 1986; 105: 179–89.PubMedGoogle Scholar
  10. 10.
    Buhl R, Jaffe HA, Holroyd KY, et al. Systemic glutathione deficiency in symptom-free HIV-sero-positive individuals. Lancet. 1989; II: 1294–8.CrossRefGoogle Scholar
  11. 11.
    Ellard GA, Gammon PT. Acetylator phenotyping of tuberculosis patients using matrix isoniazid or sulfadimidine and its prognostic significance for treatment with several intermittent isoniazid-containing regimens. Br J Clin Pharmacol. 1977; 4: 5–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Ratain MI, Mick R, Berezin F, et al. Paradoxical relationship between acetylator phenotype and amonafide toxicity. Clin Pharmacol Ther. 1991; 50: 573–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Hein DW. Acetylator genotype and arylamine-induced carcinogenesis. Acta Biochem Biophys. 1988; 948: 37–66.Google Scholar
  14. 14.
    Roots I, Drakoulis N, Brockmoller J. Polymorphic enzymes and cancer risk. Concepts, methodology and data review. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergmon Press, 1992: 815–41.Google Scholar
  15. 15.
    Yu MC, Skipper PL, Taghizadeh K, et al. Acetylator phenotype, aminobiphenyl-hemoglobin adduct levels, and bladder cancer risk in White, Black and Asian men in Los Angeles, California. J Natl Can Inst. 1994; 86: 712–6.CrossRefGoogle Scholar
  16. 16.
    Feng Y, Rustan TD, Ferguson RJ, et al. Acetylator genotypedependent formation of 2-aminofluorene-hemoglobin adducts in rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus. Toxicol Appl Pharmacol. 1994; 124: 10–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Vineis P, Bartsch H, Caporaso N, et al. Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens. Nature. 1994; 369: 154–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Hein DW, Doll MA, Rustan TD, et al. Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 alloenzymes: effect of 7 specific NAT2 nucleic acid substitutions. Cancer Res. 1995; 55: 3531–6.PubMedGoogle Scholar
  19. 19.
    McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet. 1991; 21: 42–69.PubMedCrossRefGoogle Scholar
  20. 20.
    Hoyumpa A, Schenker S. Is glucuronidation truly preserved in patients with liver disease. Hepatology. 1991; 13: 786–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Desmond PV, Smyth FE, Mashford ML. Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries. J Gastroenterol Hepatol. 1994; 9: 350–4.PubMedCrossRefGoogle Scholar
  22. 22.
    Held H, Fried F. Elimination of para-aminosalicylic acid in patients with liver disease and renal insufficiency. Chemotherapy. 1977; 23: 405–15.PubMedCrossRefGoogle Scholar
  23. 23.
    Souich P, Erill S. Metabolism of procainamide and p-aminobenzoic acid in patients with chronic liver disease. Clin Pharmacol Ther. 1977; 22: 588–95.PubMedGoogle Scholar
  24. 24.
    Pacifici GM, Viani A, Franchi M, et al. Conjugation pathways in liver disease. Br J Clin Pharmacol. 1990; 30: 427–35.PubMedCrossRefGoogle Scholar
  25. 25.
    Dowling TC, Frye RF, Matzke GR, et al. Reduced acetylation of PAH in liver disease [abstract]. Clin Pharmacol Ther. 1997; 61: 215.Google Scholar
  26. 26.
    Horvath T, Par A, Past T, et al. Disorders of biotransformation during the progression of alcoholic liver disease. Acta Physiol Hung. 1986; 4: 351–7.Google Scholar
  27. 27.
    Horvath T, Past T, Nemeth A, et al. Drug metabolism in drug induced liver diseases: pathogenetic role of active metabolites. Acta Physiol Hung. 1989; 73: 293–304.PubMedGoogle Scholar
  28. 28.
    Ahmad R, Al-Taee M. The effect of acute viral hepatitis on the activity of N-acetyltransferase. IntHepatol Commun. 1995; 3: 123–5.CrossRefGoogle Scholar
  29. 29.
    Horvath T, Past T, Tatai Z, et al. Investigation of biotransformation capacity in patients with chronic liver diseases by pharmacokinetic methods: experimental trials. Pol J Pharmacol Pharm. 1984; 36: 361–71.PubMedGoogle Scholar
  30. 30.
    Timbrell JA, Wright JM. Urinary metabolic profile of isoniazid in patients who develop isoniazid-related liver damage. Human Toxicol. 1984; 3: 485–95.CrossRefGoogle Scholar
  31. 31.
    Levi AT, Sherlock S, Walker D. Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous drug therapy. Lancet. 1968; I: 1275–9.CrossRefGoogle Scholar
  32. 32.
    Accocella G, Bonollo L, Garimoldi M, et al. Kinetics of rifampin and isoniazid administrated alone and in combination to normal subjects and patients with liver disease. Gut. 1972; 13: 47–53.CrossRefGoogle Scholar
  33. 33.
    Filho RAP, Seva-Pereira A, de Magalhaes AFN, et al. A acetilacao da isoniazida na cirrose hepatica. Rev Paul Med. 1985; 103: 276–9.Google Scholar
  34. 34.
    Levy M, Leibowitz Y, Zylber-Katz E, et al. Impairment of dipyrone’s metabolism in asymptomatic carriers of hepatitis B virus. Clin Pharmacol Ther. 1997; 62: 6–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Zylber-Katz E, Caraco Y, Granit L, et al. Dipyrone metabolism in liver disease. Clin Pharmacol Ther. 1995; 58: 198–209.PubMedCrossRefGoogle Scholar
  36. 36.
    May DG, Arns PA, Richards WO, et al. The disposition of dapsone in cirrhosis. Clin Pharmacol Ther. 1992; 51: 689–700.PubMedCrossRefGoogle Scholar
  37. 37.
    Rodopoulos N, Wisen O, Norman A. Caffeine metabolism in patients with chronic liver disease. Scand J Lab Invest. 1995; 55: 229–42.CrossRefGoogle Scholar
  38. 38.
    Denaro CP, Wilson M, Jacob P, et al. The effect of liver disease on urine caffeine metabolic ratios. Clin Pharmacol Ther. 1996; 59: 624–35.PubMedCrossRefGoogle Scholar
  39. 39.
    El-Yazigi A, Raines DA, Abdel Wahab F, et al. Relationship between antipyrine metabolism and acetylation phenotype in health and chronic liver diseases. J Clin Pharmacol. 1995; 35: 615–21.PubMedGoogle Scholar
  40. 40.
    Irshaid YM, Al-Hadid HF, Abuirjeie MA, et al. N-acetylation phenotyping using dapsone in a Jordanian population. Br J Clin Pharmacol. 1991; 32: 289–93.PubMedCrossRefGoogle Scholar
  41. 41.
    Horai Y, Ishizaki T. N-acetylation polymorphism of dapsone in Japanese population. Br J Clin Pharmacol. 1988; 25: 487–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Tang BK, Kadar D, Qian L, et al. Caffeine as a metabolic probe: validation of its use for acetylator phenotyping. Clin Pharmacol Ther. 1991; 49: 648–57.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Micha Levy
    • 1
  • Yoseph Caraco
    • 1
  • Gerd Geisslinger
    • 2
  1. 1.Clinical Pharmacology Unit, Division of MedicineHadassah University HospitalJerusalemIsrael
  2. 2.Department of Experimental and Clinical Pharmacology and ToxicologyUniversity of Erlangen-NürnbergErlangenGermany

Personalised recommendations