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Drugs and the Liver

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Atlas of the Liver

Part of the book series: Atlas of Diseases

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Abstract

Strategically located between the splanchnic and systemic circulations and equipped with a vast array of enzymes, the liver functions as a major organ of drug metabolism. Drugs presented to the liver may follow one of several possible fates. First, an inactive agent or prodrug may be metabolized to its pharmacologically active form. Second, an already active drug may be rendered into inactive metabolites and eliminated from the body. Third, the biotransformation of a pharmacologic agent may lead to the formation of products that cause damage to the liver or other organs. Finally, drug metabolism may lead to carcinogenesis.

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References

  1. Watkins PB: Role of cytochrome P450 in drug metabolism and hepatotoxicity. Semiti Liver Dis 1990, 10:235–250.

    Article  CAS  Google Scholar 

  2. Alvares A, Pratt WB: Pathways of drug metabolism. In Principles of Drug Action: The Basis of Pharmacology. Edited by Pratt WB, Taylor P. New York: Churchill-Livingstone; 1990:365–422.

    Google Scholar 

  3. Boelsterli UA: Mechanisms underlying the hepatotoxicity of nonsteroidal anti-inflammatory drugs. In Drug-induced Liver Disease. Edited by Kaplowitz N, DeLeve LD. New York: Marcel Dekker; 2003:345–376.

    Google Scholar 

  4. Meyer UA: Drug metabolism in health and disease. In Extrahepatic Manifestations in Liver Diseases. Edited by Schmid R, Bianchi L, Gerok W, Maier KP. Dordrecht/Boston/London: Kluwer Academic g; 1993:286–295.

    Google Scholar 

  5. Hoyumpa A, Schenker S: Influence of liver disease in the disposition and elimination of drugs. In Diseases of the Liver. Edited by Schiff L, Schiff E. Philadelphia: JB Lippincott; 1993:784–824.

    Google Scholar 

  6. Caporaso N, Landi MX Vineis P: Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemiologic evidence. Pharmacogenetics 1991, 1:4–9.

    Article  CAS  PubMed  Google Scholar 

  7. Agundez JAG, Ledesma MC, Benitez J, et al.: CYP2D6 genes and risk of liver cancer. Lancet 1995, 345:830–831.

    Article  CAS  PubMed  Google Scholar 

  8. Yamazaki H, Inui Y, Yun CH, et al.: Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. Carcinogenesis 1992, 13:1789–1794.

    Article  CAS  PubMed  Google Scholar 

  9. Benet LZ, Cummins CL: The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Delivery Rev 2001, 50:S3–S11.

    Article  CAS  Google Scholar 

  10. Cummins CL, Jacobsen W, Benet LZ: Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4.J Pharmacol Exp Ther 2002, 300:1036–1045.

    Article  CAS  PubMed  Google Scholar 

  11. Roberts R, Wilkinson GR, Branch RA, et al.: Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide. Gastroenterology 1978, 75:479–485.

    CAS  PubMed  Google Scholar 

  12. 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, 347–359.

    Google Scholar 

  13. Greenblatt DJ, Allen MD, Harmatz JS, et al.: Diazepam disposition determinants. Clin Pharmacol Ther 1980, 27:301–312.

    Article  CAS  PubMed  Google Scholar 

  14. Andreasen PB, Hendel J, Greisen G, et al.: Pharmacokinetics of diazepam in disordered liver function. Eur J Clin Pharmacol 1976, 10:115–120.

    Article  CAS  PubMed  Google Scholar 

  15. Branch RA, Morgan MH, James J, et al.: Intravenous administration of diazepam in patients with chronic liver disease. Gut 1976, 17:975–983.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Sim SM, Back DJ, Breckenridge AM: The effect of various drugs on the glucuronidation of zidovudine (azidothymidine, AZT) by human liver microsomes. Br J Clin Pharmacol 1991, 32:17–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Sonne J, Andreason PB, Loft S, et al.: Glucuronidation of oxazepam is not spared in patients with hepatic encephalopathy. Hepatology 1990, 11:951–956.

    Article  CAS  PubMed  Google Scholar 

  20. McLean AJ, Cogger VC, Chong GC, et al.: Age-related pseudocapillarization of the human liver.J Pathol 2003, 200:112–117.

    Article  PubMed  Google Scholar 

  21. Le Couteur DG, Cogger VC, Markus AM, et al.: Pseudocapillarization and associated energy limitation in the aged rat liver. Hepatology 2001, 33:537–543.

    Article  PubMed  Google Scholar 

  22. Froomes PRA, Morgan DJ, Smallwood RA, Angus PW: Comparative effects of oxygen supplementation on theophylline and acetaminophen clearance in human cirrhosis. Gastroenterology 1999, 116:915–920.

    Article  CAS  PubMed  Google Scholar 

  23. Hoyumpa A, Schenker S: Is glucuronidation truly preserved in patients with liver disease? Hepatology 1991, 13:786–795.

    Article  CAS  PubMed  Google Scholar 

  24. Kaplowitz N: Drug metabolism and hepatotoxicity. In Liver and Biliary Diseases. Edited by Kaplowitz N. Baltimore: Williams & Wilkins; 1992:82–97.

    Google Scholar 

  25. Desmet VJ: Drug-induced liver disease: pathogenetic mechanisms and histopathological lesions. Medical Intelligence 1994, 2:36–47.

    Google Scholar 

  26. Lee WM: Drug-induced hepatotoxicity [review]. Aliment Pharmacol Ther 1993, 7:477–483.

    Article  CAS  PubMed  Google Scholar 

  27. Farrell G. Drug-induced liver disease. London: Churchill-Livingstone; 1994.

    Google Scholar 

  28. Rinder HM, Love JC, Wexler R: Amiodarone hepatotoxicity. N Engl J Med 1986, 314:318.

    CAS  PubMed  Google Scholar 

  29. Goldman IS, Winkler ML, Raper SE, et al.: Increased hepatic density and phospholipidosis due to amiodarone. AJR Am J Roentgenol 1985, 144:541–546.

    Article  CAS  PubMed  Google Scholar 

  30. Poucell S, et al.: Abstract. Hepatology 1985, 5:995.

    Google Scholar 

  31. Kaplowitz M: Drug-induced liver disorders: introduction and overview. In Drug-induced Liver Disease. Edited by Kaplowitz N, DeLeve D. New York: Marcel Dekker; 2003:1–14.

    Google Scholar 

  32. Nelson SD: Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990, 10:267–278.

    Article  CAS  PubMed  Google Scholar 

  33. Fiorucci S, Antonelli E, Mencarelli A, et al.: A NO-releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway. Br J Pharmacol 2002, 135:589–599.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. McNeil L, Allen M, Estrada C, Cooh P: Pyrazimide and rifampin vs isoniazid for the treatment of latent tuberculosis. Chest 2003, 123:102–106.

    Article  Google Scholar 

  35. Sarma GR, Immanuel C, Kailsam S, et al.: Rifampin-induced release of hydralazine from isoniazid. Am Rev Resp Dis 1986, 133:1072–1075.

    CAS  PubMed  Google Scholar 

  36. Steele MA, Burk RI, Des Prez RM: Toxic hepatitis with isoniazid and rifampin. Chest 1991, 99:465–471.

    Article  CAS  PubMed  Google Scholar 

  37. Blair IA, Tinoco RM, Brodie MJ, et al.: Plasma hydrazine concentrations in man after isoniazid and hydrazine administration. Hum Toxicol 1985, 4:195–202.

    Article  CAS  PubMed  Google Scholar 

  38. Kanel GC, Cassidy W, Shuster L, et al.: Cocaine-induced liver injury: comparison of morphological features in man and in experimental models. Hepatology 1990, 11:646–651.

    Article  CAS  PubMed  Google Scholar 

  39. Wanless IR, Dore S, Gopinath N, et al.: Histopathology of cocaine hepatotoxicity. Gastroenterology 1990, 98:497–501.

    CAS  PubMed  Google Scholar 

  40. Peterson FJ, Knodell RG, Lindemann NJ, et al.: Prevention of acetaminophen and cocaine hepatotoxicity in mice by Cimetidine treatment. Gastroenterology 1983, 85:122–129.

    CAS  PubMed  Google Scholar 

  41. Bay MK, Schenker S: Interactions between alcohol and other hepatotoxins. In Alcoholic Liver Disease: Pathology and Pathogenesis. Edited by Hall P, Coffelt N. London: Edward Arnold; 1995:260–278.

    Google Scholar 

  42. Kenna JG, VanFelt FN: The metabolism and toxicity of inhaled anaesthetic agents. Anaesth Pharmacol Rev 1994, 2:29–42.

    CAS  Google Scholar 

  43. Elliot RH, Strunin L: Hepatotoxicity of volatile anaesthetics. Br J Anaesthesia 1993, 70:339–348.

    Article  Google Scholar 

  44. Kenna JG, Neuberger JM: Immuno-pathogenesis and treatment of halothane hepatitis. Clin Immunother 1996, 3:108–124.

    Article  Google Scholar 

  45. Eliasson E, Kenna JG: Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol Pharmacol 1996, 50:573–582.

    CAS  PubMed  Google Scholar 

  46. Kenna JG: Immunoallergic drug-induced hepatitis: lessons from halothane.J Hepatology 1997, 26 (suppl I):5–12.

    Article  CAS  Google Scholar 

  47. Robin M-A, LeRoy M, Descatoire V, et al.: Plasma membrane P450 as neoantigens and autoimmune targets in drug induced hepatitis.J Hepatology 1997, 26 (Suppl l):23–30.

    Article  CAS  Google Scholar 

  48. Heubi JE, Partin JC, Partin JS, et al.: Reye’s syndrome: current concepts. Hepatology 1987, 7:155–164.

    Article  CAS  PubMed  Google Scholar 

  49. Deschamps D, DeBeco V, Fisch C, et al.: Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions. Hepatology 1994, 19:948–961.

    Article  CAS  PubMed  Google Scholar 

  50. Fromenty B, Berson A, Pessayre D: Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation.J Hepatol 1997, 26 (suppl l):13–22.

    Article  CAS  PubMed  Google Scholar 

  51. Chan TY: The prevalence, use and harmful potential in some Chinese herbal medicines in babies and children. Vet Hum Toxicol 1994, 36:238–240.

    CAS  PubMed  Google Scholar 

  52. Yeung CY, Lee FT, Wong HN: Effect of a popular Chinese herb on neonatal bilirubin protein binding. Biol Neonate 1990, 58:98–103.

    Article  CAS  PubMed  Google Scholar 

  53. DeLeve LD, McCuskey RS, Wang X, et al.: Characterization of a reproducible rat model of hepatic veno-occlusive disease. Hepatology 1999,29:1779–1791.

    Article  CAS  PubMed  Google Scholar 

  54. DeLeve LD, Wang X, Kuhlenkamp JF, Kaplowitz N: Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: the role of glutathione and relevance to hepatic venooclusive disease. Hepatology 1996, 23:589–599.

    Article  CAS  PubMed  Google Scholar 

  55. DeLeve LD, Ito I, Bethea NW, et al.: Embolization by sinusoidal lining cell obstructs the microcirculation in rat sinusoidal obstruction syndrome (hepatic venooclusive disease). Am J Physiol-Gastrointest Liver Physiol 2003, in press.

    Google Scholar 

  56. Kim H-Y, Stermitz FR, Molyneaux RJ, et al.: Structural influences on pyrrolizadine alkaloid-induced cytopathology. Toxicol Appl Pharmacol 1993, 122:61–69.

    Article  CAS  PubMed  Google Scholar 

  57. Huxtable RJ: Activation and pulmonary toxicity of pyrrolizidine alkaloids. Pharmacol Ther 1990, 47:371–389.

    Article  CAS  PubMed  Google Scholar 

  58. Cheeke PR: A review of the functional and evolutionary roles of the liver in the detoxification of poisonous plants, with special reference to pyrrolizidine alkaloids. Vet Hum Toxicol 1994, 240–247.

    Google Scholar 

  59. Loeper J, Descatoire V, Letteron P, et al.: Hepatotoxicity of germander in mice. Gastroenterology 1994, 106:464–472.

    CAS  PubMed  Google Scholar 

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Authors
  1. Laurie D. DeLeve
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  2. Anastacio M. Hoyumpa
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  3. Steven Schenker
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Editor information

Editors and Affiliations

  1. Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA

    Willis C. Maddrey MD, MACP (Executive Vice President for Clinical Affairs, Adelyn and Edmund M. Hoffman Distinguished Chair in Medical Science, Arnold N. and Carol S. Ablon Professor in Biomedical Sciences; Professor) (Executive Vice President for Clinical Affairs, Adelyn and Edmund M. Hoffman Distinguished Chair in Medical Science, Arnold N. and Carol S. Ablon Professor in Biomedical Sciences; Professor)

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DeLeve, L.D., Hoyumpa, A.M., Schenker, S. (2004). Drugs and the Liver. In: Maddrey, W.C. (eds) Atlas of the Liver. Atlas of Diseases. Current Medicine Group, London. https://doi.org/10.1007/978-1-4615-6502-4_6

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  • DOI: https://doi.org/10.1007/978-1-4615-6502-4_6

  • Publisher Name: Current Medicine Group, London

  • Print ISBN: 978-1-4615-6504-8

  • Online ISBN: 978-1-4615-6502-4

  • eBook Packages: Springer Book Archive

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