Chapter 2 Drug-Induced Hepatotoxicity: Learning from Recent Cases of Drug Attrition

Advances in Molecular Toxicology

Volumn 2, Issue C, 2008, Pages 25-56

  Pähler, Axel ^a   Funk, Christoph ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

BOSENTAN; BROMFENAC; BUSPIRONE; DRUG; FELBAMATE; GLIBENCLAMIDE; ISONIAZID; KETOCONAZOLE; NEFAZODONE; PARACETAMOL; PIOGLITAZONE; ROSIGLITAZONE; TIENILIC ACID; TOLCAPONE; TRAZODONE; TROGLITAZONE; TROVAFLOXACIN; VALPROIC ACID;

ADVERSE DRUG REACTION; CAUSE OF DEATH; CHOLESTASIS; DRUG ATTRITION; DRUG INDUCED DISEASE; DRUG SAFETY; GENOTOXICITY; HUMAN; INTRAHEPATIC CHOLESTASIS; LIVER INJURY; LIVER TOXICITY; METABOLIC ACTIVATION; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW; TERATOGENICITY;

EID: 67649949488     PISSN: 18720854     EISSN: None     Source Type: Book Series    
DOI: 10.1016/S1872-0854(07)02002-4     Document Type: Review

References (97)

1. Kola I., and Landis J. Can the pharmaceutical industry reduce attrition rates?. Nat. Rev. Drug Discov. 3 (2004) 711-715
2. Prentis R.A., Lis Y., and Walker S.R. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). Br. J. Clin. Pharmacol. 25 (1988) 387-396
3. Olivier P., and Montastruc J.L. The nature of the scientific evidence leading to drug withdrawals for pharmacovigilance reasons in France. Pharmacoepidemiol. Drug Saf. 15 (2006) 808-812
4. Nassar A.E., Kamel A.M., and Clarimont C. Improving the decision-making process in structural modification of drug candidates: reducing toxicity. Drug Discov. Today 9 (2004) 1055-1064
5. Ballet F. Hepatotoxicity in drug development: detection, significance and solutions. J. Hepatol. 26 Suppl. 2 (1997) 26-36
6. Larson A.M., Polson J., Fontana R.J., Davern T.J., Lalani E., Hynan L.S., Reisch J.S., Schiodt F.V., Ostapowicz G., Shakil A.O., and Lee W.M. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42 (2005) 1364-1372
7. Navarro V.J., and Senior J.R. Drug-related hepatotoxicity. N. Engl. J. Med. 354 (2006) 731-739
8. Walgren J.L., Mitchell M.D., and Thompson D.C. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit. Rev. Toxicol. 35 (2005) 325-361
9. Chen C. Troglitazone: an antidiabetic agent. Am. J. Health Syst. Pharm. 55 (1998) 905-925
10. Gitlin N., Julie N.L., Spurr C.L., Lim K.N., and Juarbe H.M. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann. Intern. Med. 129 (1998) 36-38
11. Herrine S.K., and Choudhary C. Severe hepatotoxicity associated with troglitazone. Ann. Intern. Med. 130 (1999) 163-164
12. Shibuya A., Watanabe M., Fujita Y., Saigenji K., Kuwao S., Takahashi H., and Takeuchi H. An autopsy case of troglitazone-induced fulminant hepatitis. Diabetes Care 21 (1998) 2140-2143
13. Aranda-Michel J., Koehler A., Bejarano P.A., Poulos J.E., Luxon B.A., Khan C.M., Ee L.C., Balistreri W.F., and Weber Jr. F.L. Nefazodone-induced liver failure: report of three cases. Ann. Intern. Med. 130 (1999) 285-288
14. Choi S. Nefazodone (serzone) withdrawn because of hepatotoxicity. Can. Med. Assoc. J. 169 (2003) 1187
15. Lucena M.I., Andrade R.J., Gomez-Outes A., Rubio M., and Cabello M.R. Acute liver failure after treatment with nefazodone. Digest Dis. Sci. 44 (1999) 2577-2579
16. Lucena M.I., Carvajal A., Andrade R.J., and Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin. Drug Saf. 2 (2003) 249-262
17. Stewart D.E. Hepatic adverse reactions associated with nefazodone. Can. J. Psychiat. 47 (2002) 375-377
18. Smith M.T. Mechanisms of troglitazone hepatotoxicity. Chem. Res. Toxicol. 16 (2003) 679-687
19. Masubuchi Y. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21 (2006) 347-356
20. Ju C., and Uetrecht J.P. Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr. Drug Metab. 3 (2002) 367-377
21. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu. Rev. Pharmacol. Toxicol. 47 (2007) 513-539
22. Uetrecht J.P. New concepts in immunology relevant to idiosyncratic drug reactions: the "danger hypothesis" and innate immune system. Chem. Res. Toxicol. 12 (1999) 387-395
23. Uetrecht J.P. Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions?. Curr. Drug Metab. 1 (2000) 133-141
24. Kalgutkar A.S., Gardner I., Obach R.S., Shaffer C.L., Callegari E., Henne K.R., Mutlib A.E., Dalvie D.K., Lee J.S., Nakai Y., O'Donnell J.P., Boer J., and Harriman S.P. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 6 (2005) 161-225
25. Zhou S., Chan E., Duan W., Huang M., and Chen Y.Z. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab. Rev. 37 (2005) 41-213
26. Dipple A. DNA adducts of chemical carcinogens. Carcinogenesis 16 (1995) 437-441
27. Uetrecht J. Role of drug metabolism for breaking tolerance and the localization of drug hypersensitivity. Toxicology 209 (2005) 113-118
28. Nelson S.D. Structure toxicity relationships - how useful are they in predicting toxicities of new drugs?. Adv. Exp. Med. Biol. 500 (2001) 33-43
29. Forman L.M., Simmons D.A., and Diamond R.H. Hepatic failure in a patient taking rosiglitazone. Ann. Intern. Med. 132 (2000) 118-121
30. May L.D., Lefkowitch J.H., Kram M.T., and Rubin D.E. Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann. Intern. Med. 136 (2002) 449-452
31. Tettey J.N., Maggs J.L., Rapeport W.G., Pirmohamed M., and Park B.K. Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo. Chem. Res. Toxicol. 14 (2001) 965-974
32. Kawai K., Kawasaki-Tokui Y., Odaka T., Tsuruta F., Kazui M., Iwabuchi H., Nakamura T., Kinoshita T., Ikeda T., Yoshioka T., Komai T., and Nakamura K. Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. Arzneimittelforschung 47 (1997) 356-368
33. Kassahun K., Pearson P.G., Tang W., McIntosh I., Leung K., Elmore C., Dean D., Wang R., Doss G., and Baillie T.A. Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem. Res. Toxicol. 14 (2001) 62-70
34. Prabhu S., Fackett A., Lloyd S., McClellan H.A., Terrell C.M., Silber P.M., and Li A.P. Identification of glutathione conjugates of troglitazone in human hepatocytes. Chem. Biol. Interact. 142 (2002) 83-97
35. Soglia J.R., Harriman S.P., Zhao S., Barberia J., Cole M.J., Boyd J.G., and Contillo L.G. The development of a higher throughput reactive intermediate screening assay incorporating micro-bore liquid chromatography-micro-electrospray ionization-tandem mass spectrometry and glutathione ethyl ester as an in vitro conjugating agent. J. Pharm. Biomed. Anal. 36 (2004) 105-116
36. Alvarez-Sanchez R., Montavon F., Hartung T., and Pahler A. Thiazolidinedione bioactivation: a comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry. Chem. Res. Toxicol. 19 (2006) 1106-1116
37. Sahi J., Black C.B., Hamilton G.A., Zheng X., Jolley S., Rose K.A., Gilbert D., LeCluyse E.L., and Sinz M.W. Comparative effects of thiazolidinediones on in vitro p450 enzyme induction and inhibition. Drug Metab. Dispos. 31 (2003) 439-446
38. Kiyota Y., Kondo T., Maeshiba Y., Hashimoto A., Yamashita K., Yoshimura Y., Motohashi M., and Tanayama S. Studies on the metabolism of the new antidiabetic agent pioglitazone. Identification of metabolites in rats and dogs. Arzneimittelforschung 47 (1997) 22-28
39. Shen Z., Reed J.R., Creighton M., Liu D.Q., Tang Y.S., Hora D.F., Feeney W., Szewczyk J., Bakhtiar R., Franklin R.B., and Vincent S.H. Identification of novel metabolites of pioglitazone in rat and dog. Xenobiotica 33 (2003) 499-509
40. Baughman T.M., Graham R.A., Wells-Knecht K., Silver I.S., Tyler L.O., Wells-Knecht M., and Zhao Z. Metabolic activation of pioglitazone identified from rat and human liver microsomes and freshly isolated hepatocytes. Drug Metab. Dispos. 33 (2005) 733-738
41. Cox P.J., Ryan D.A., Hollis F.J., Harris A.M., Miller A.K., Vousden M., and Cowley H. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. Drug Metab. Dispos. 28 (2000) 772-780
42. Carvajal Garcia-Pando A., Garcia del Pozo J., Sanchez A.S., Velasco M.A., Rueda de Castro A.M., and Lucena M.I. Hepatotoxicity associated with the new antidepressants. J. Clin. Psychiat. 63 (2002) 135-137
43. Greene D.S., and Barbhaiya R.H. Clinical pharmacokinetics of nefazodone. Clin. Pharmacokinet. 33 (1997) 260-275
44. Rotzinger S., and Baker G.B. Human cyp3a4 and the metabolism of nefazodone and hydroxynefazodone by human liver microsomes and heterologously expressed enzymes. Eur. Neuropsychopharmacol. 12 (2002) 91-100
45. Mayol R.F., Cole C.A., Luke G.M., Colson K.L., and Kerns E.H. Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma. Drug Metab. Dispos. 22 (1994) 304-311
46. Peterman S.M., Duczak Jr. N., Kalgutkar A.S., Lame M.E., and Soglia J.R. Application of a linear ion trap/orbitrap mass spectrometer in metabolite characterization studies: examination of the human liver microsomal metabolism of the non-tricyclic anti-depressant nefazodone using data-dependent accurate mass measurements. J. Am. Soc. Mass Spectrom. 17 (2006) 363-375
47. Kaul S., Shukla U.A., and Barbhaiya R.H. Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses. J. Clin. Pharmacol. 35 (1995) 830-839
48. von Moltke L.L., Greenblatt D.J., Granda B.W., Grassi J.M., Schmider J., Harmatz J.S., and Shader R.I. Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and p450-3a4 inhibitory actions. Psychopharmacology (Berl) 145 (1999) 113-122
49. Rotzinger S., Fang J., Coutts R.T., and Baker G.B. Human cyp2d6 and metabolism of m-chlorophenylpiperazine. Biol. Psychiat. 44 (1998) 1185-1191
50. Kalgutkar A.S., Vaz A.D., Lame M.E., Henne K.R., Soglia J., Zhao S.X., Abramov Y.A., Lombardo F., Collin C., Hendsch Z.S., and Hop C.E. Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome p450 3a4. Drug Metab. Dispos. 33 (2005) 243-253
51. Beck P.L., Bridges R.J., Demetrick D.J., Kelly J.K., and Lee S.S. Chronic active hepatitis associated with trazodone therapy. Ann. Intern. Med. 118 (1993) 791-792
52. Fernandes N.F., Martin R.R., and Schenker S. Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity. Am. J. Gastroenterol. 95 (2000) 532-535
53. Rettman K.S., and McClintock C. Hepatotoxicity after short-term trazodone therapy. Ann. Pharmacother. 35 (2001) 1559-1561
54. Jauch R., Kopitar Z., Prox A., and Zimmer A. Pharmacokinetics and metabolism of trazodone in man (Author's Trans.). Arzneimittelforschung 26 (1976) 2084-2089
55. Baiocchi L., Frigerio A., Giannangeli M., and Palazzo G. Basic metabolites of trazodone in humans. Arzneimittelforschung 24 (1974) 1699-1706
56. Kalgutkar A.S., Henne K.R., Lame M.E., Vaz A.D., Collin C., Soglia J.R., Zhao S.X., and Hop C.E. Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant p4503a4. Chem. Biol. Interact. 155 (2005) 10-20
57. Rotzinger S., Fang J., and Baker G.B. Trazodone is metabolized to m-chlorophenylpiperazine by cyp3a4 from human sources. Drug Metab. Dispos. 26 (1998) 572-575
58. Kivisto K.T., Lamberg T.S., Kantola T., and Neuvonen P.J. Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. Clin. Pharmacol. Ther. 62 (1997) 348-354
59. Jajoo H.K., Mayol R.F., LaBudde J.A., and Blair I.A. Metabolism of the antianxiety drug buspirone in human subjects. Drug Metab. Dispos. 17 (1989) 634-640
60. Jajoo H.K., Blair I.A., Klunk L.J., and Mayol R.F. In vitro metabolism of the antianxiety drug buspirone as a predictor of its metabolism in vivo. Xenobiotica 20 (1990) 779-786
61. Gammans R.E., Mayol R.F., and LaBudde J.A. Metabolism and disposition of buspirone. Am. J. Med. 80 (1986) 41-51
62. Caccia S., Ballabio M., Samanin R., Zanini M.G., and Garattini S. (-)-m-Chlorophenyl-piperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J. Pharm. Pharmacol. 33 (1981) 477-478
63. Preininger K., Stingl H., Englisch R., Furnsinn C., Graf J., Waldhausl W., and Roden M. Acute troglitazone action in isolated perfused rat liver. Br. J. Pharmacol. 126 (1999) 372-378
64. Krivoy N., Zaher A., Yaacov B., and Alroy G. Fatal toxic intrahepatic cholestasis secondary to glibenclamide. Diabetes Care 19 (1996) 385-386
65. Fukano M., Amano S., Sato J., Yamamoto K., Adachi H., Okabe H., Fujiyama Y., and Bamba T. Subacute hepatic failure associated with a new antidiabetic agent, troglitazone: a case report with autopsy examination. Hum. Pathol. 31 (2000) 250-253
66. Funk C., Pantze M., Jehle L., Ponelle C., Scheuermann G., Lazendic M., and Gasser R. Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (bsep) by troglitazone and troglitazone sulfate. Toxicology 167 (2001) 83-98
67. Funk C., Ponelle C., Scheuermann G., and Pantze M. Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (bsep) in the rat. Mol. Pharmacol. 59 (2001) 627-635
68. Kostrubsky V.E., Vore M., Kindt E., Burliegh J., Rogers K., Peter G., Altrogge D., and Sinz M.W. The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats. Drug Metab. Dispos. 29 (2001) 1561-1566
69. Ott P., Ranek L., and Young M.A. Pharmacokinetics of troglitazone, a ppar-gamma agonist, in patients with hepatic insufficiency. Eur. J. Clin. Pharmacol. 54 (1998) 567-571
70. Kostrubsky S.E., Strom S.C., Kalgutkar A.S., Kulkarni S., Atherton J., Mireles R., Feng B., Kubik R., Hanson J., Urda E., and Mutlib A.E. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. 90 (2006) 451-459
71. Tafazoli S., Spehar D.D., and O'Brien P.J. Oxidative stress mediated idiosyncratic drug toxicity. Drug Metab. Rev. 37 (2005) 311-325
72. Narayanan P.K., Hart T., Elcock F., Zhang C., Hahn L., McFarland D., Schwartz L., Morgan D.G., and Bugelski P. Troglitazone-induced intracellular oxidative stress in rat hepatoma cells: a flow cytometric assessment. Cytometry A 52 (2003) 28-35
73. Tirmenstein M.A., Hu C.X., Gales T.L., Maleeff B.E., Narayanan P.K., Kurali E., Hart T.K., Thomas H.C., and Schwartz L.W. Effects of troglitazone on hepg2 viability and mitochondrial function. Toxicol. Sci. 69 (2002) 131-138
74. Hewitt N.J., Lloyd S., Hayden M., Butler R., Sakai Y., Springer R., Fackett A., and Li A.P. Correlation between troglitazone cytotoxicity and drug metabolic enzyme activities in cryopreserved human hepatocytes. Chem. Biol. Interact. 142 (2002) 73-82
75. Kostrubsky V.E., Sinclair J.F., Ramachandran V., Venkataramanan R., Wen Y.H., Kindt E., Galchev V., Rose K., Sinz M., and Strom S.C. The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures. Drug Metab. Dispos. 28 (2000) 1192-1197
76. Honma W., Shimada M., Sasano H., Ozawa S., Miyata M., Nagata K., Ikeda T., and Yamazoe Y. Phenol sulfotransferase, st1a3, as the main enzyme catalyzing sulfation of troglitazone in human liver. Drug Metab. Dispos. 30 (2002) 944-949
77. Trauner M., Meier P.J., and Boyer J.L. Molecular pathogenesis of cholestasis. N. Engl. J. Med. 339 (1998) 1217-1227
78. Strautnieks S.S., Bull L.N., Knisely A.S., Kocoshis S.A., Dahl N., Arnell H., Sokal E., Dahan K., Childs S., Ling V., Tanner M.S., Kagalwalla A.F., Nemeth A., Pawlowska J., Baker A., Mieli-Vergani G., Freimer N.B., Gardiner R.M., and Thompson R.J. A gene encoding a liver-specific abc transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20 (1998) 233-238
79. Noe J., Kullak-Ublick G.A., Jochum W., Stieger B., Kerb R., Haberl M., Mullhaupt B., Meier P.J., and Pauli-Magnus C. Impaired expression and function of the bile salt export pump due to three novel abcb11 mutations in intrahepatic cholestasis. J. Hepatol. 43 (2005) 536-543
80. Menon K.V.N., Angulo P., and Lindor K.D. Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus. Am. J. Gastroenterol. 96 (2001) 1631-1634
81. Loi C.M., Young M., Randinitis E., Vassos A., and Koup J.R. Clinical pharmacokinetics of troglitazone. Clin. Pharmacokinet. 37 (1999) 91-104
82. Loi C.M., Alvey C.W., Vassos A.B., Randinitis E.J., Sedman A.J., and Koup J.R. Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites. J. Clin. Pharmacol. 39 (1999) 920-926
83. Baillie T.A., and Kassahun K. Biological reactive intermediates in drug discovery and development: a perspective from the pharmaceutical industry. Adv. Exp. Med. Biol. 500 (2001) 45-51
84. Evans D.C., Watt A.P., Nicoll-Griffith D.A., and Baillie T.A. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17 (2004) 3-16
85. Day S.H., Mao A., White R., Schulz-Utermoehl T., Miller R., and Beconi M.G. A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J. Pharmacol. Toxicol. Methods 52 (2005) 278-285
86. Sabbioni G. Hemoglobin binding of aromatic amines: molecular dosimetry and quantitative structure-activity relationships for n-oxidation. Environ. Health Perspect. 99 (1993) 213-216
87. Hatch F.T., and Colvin M.E. Quantitative structure-activity (qsar) relationships of mutagenic aromatic and heterocyclic amines. Mutat. Res. 376 (1997) 87-96
88. Yan Z., Rafferty B., Caldwell G.W., and Masucci J.A. Rapidly distinguishing reversible and irreversible cyp450 inhibitors by using fluorometric kinetic analyses. Eur. J. Drug Metab. Pharmacokinet. 27 (2002) 281-287
89. Baillie T.A., and Davis M.R. Mass spectrometry in the analysis of glutathione conjugates. Biol. Mass Spectrom. 22 (1993) 319-325
90. Caldwell G.W., and Yan Z. Screening for reactive intermediates and toxicity assessment in drug discovery. Curr. Opin. Drug Discov. Devel. 9 (2006) 47-60
91. Dieckhaus C.M., Fernandez-Metzler C.L., King R., Krolikowski P.H., and Baillie T.A. Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem. Res. Toxicol. 18 (2005) 630-638
92. Smith D.A., and Obach R.S. Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab. Dispos. 33 (2005) 1409-1417
93. Smith D.A., and Obach R.S. Metabolites and safety: what are the concerns, and how should we address them?. Chem. Res. Toxicol. 19 (2006) 1570-1579
94. Stieger B., Fattinger K., Madon J., Kullak-Ublick G.A., and Meier P.J. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (bsep) of rat liver. Gastroenterology 118 (2000) 422-430
95. Hirano H., Kurata A., Onishi Y., Sakurai A., Saito H., Nakagawa H., Nagakura M., Tarui S., Kanamori Y., Kitajima M., and Ishikawa T. High-speed screening and qsar analysis of human atp-binding cassette transporter abcb11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis. Mol. Pharm. 3 (2006) 252-265
96. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov. 4 (2005) 489-499
97. Peters T.S. Do preclinical testing strategies help predict human hepatotoxic potentials?. Toxicol. Pathol. 33 (2005) 146-154