Strategies and chemical design approaches to reduce the potential for formation of reactive metabolic species

Current Topics in Medicinal Chemistry

Volumn 11, Issue 4, 2011, Pages 419-449

  Argikar, Upendra A ^a   Mangold, James B ^a   Harriman, Shawn P ^a  

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

Bioactivation; Chemical design approach; Covalent protein binding; Isosteres; Reactive intermediates; Structural alerts

Indexed keywords

DNA;

APOPTOSIS; ARTICLE; CELL DEATH; COVALENT BOND; IN VIVO STUDY; MACROMOLECULE; METABOLIC ACTIVATION; NECROSIS; OXIDATIVE STRESS; TOXICITY;

ANIMALS; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; HUMANS; PHARMACEUTICAL PREPARATIONS;

EID: 79551679354     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802611794480891     Document Type: Article

References (122)

1. Nelson, S. D. Structure toxicity relationships--how useful are they in predicting toxicities of new drugs? Adv. Exp. Med. Biol., 2001, 500, 33-43.
2. Kalgutkar, A. S.; Driscoll, J.; Zhao, S. X.; Walker, G. S.; Shepard, R. M.; Soglia, J. R.; Atherton, J.; Yu, L.; Mutlib, A. E.; Munchhof, M. J.; Reiter, L. A.; Jones, C. S.; Doty, J. L.; Trevena, K. A.; Shaffer, C. L.; Ripp, S. L. A rational chemical intervention strategy to circumvent bioactivation liabilities associated with a nonpeptidyl thrombopoietin receptor agonist containing a 2-amino-4-arylthiazole motif. Chem. Res. Toxicol., 2007, 20, 1954-1965.
3. 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.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab., 2005, 6, 161-225.
4. Kalgutkar, A. S.; Obach, R. S.; Maurer, T. S. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drugdrug interactions and idiosyncratic adverse drug reactions. Curr. Drug Metab., 2007, 8, 407-447.
5. Prakash, C.; Sharma, R.; Gleave, M.; Nedderman, A. In vitro screening techniques for reactive metabolites for minimizing bioactivation potential in drug discovery. Curr. Drug Metab., 2008, 9,952-964.
6. Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O'Donnell, J. P. Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem. Res. Toxicol., 2002, 15, 269-299.
7. Zhuo, X.; Hartz, R. A.; Bronson, J. J.; Wong, H.; Ahuja, V. T.; Vrudhula, V. M.; Leet, J. E.; Huang, S.; Macor, J. E.; Shu, Y. Z. Comparative biotransformation of pyrazinone-containing corticotropin-releasing factor receptor-1 antagonists: minimizing the reactive metabolite formation. Drug Metab. Dispos., 2010, 38, 5-15.
8. Kalgutkar, A. S.; Dalvie, D. K.; O'Donnell, J. P.; Taylor, T. J.; Sahakian, D. C. On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics. Curr. Drug Metab., 2002, 3, 379-424.
9. Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol., 2004, 17, 3-16.
10. Nelson, S. D. Mechanisms of the formation and disposition of reactive metabolites that can cause acute liver injury. Drug Metab. Rev., 1995, 27, 147-177.
11. Kalgutkar, A. S.; Soglia, J. R. Minimising the potential for metabolic activation in drug discovery. Expert. Opin. Drug Metab. Toxicol., 2005, 1, 91-142.
12. Lazarou, J.; Pomeranz, B. H.; Corey, P. N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA, 1998, 279, 1200-1205.
13. Pirmohamed, M.; Breckenridge, A. M.; Kitteringham, N. R.; Park, B. K. Adverse drug reactions. BMJ, 1998, 316, 1295-1298.
14. Jefferys, D. B.; Leakey, D.; Lewis, J. A.; Payne, S.; Rawlins, M. D. New active substances authorized in the United Kingdom between1972 and 1994. Br. J. Clin. Pharmacol., 1998, 45, 151-156.
15. Issa, A. M.; Phillips, K. A.; Van Bebber, S.; Nidamarthy, H. G.; Lasser, K. E.; Haas, J. S.; Alldredge, B. K.; Wachter, R. M.; Bates, D. W. Drug withdrawals in the United States: a systematic review of the evidence and analysis of trends. Curr. Drug Saf., 2007, 2, 177-185.
16. Gunawan, B.; Kaplowitz, N. Clinical perspectives on xenobioticinduced hepatotoxicity. Drug Metab. Rev., 2004, 36, 301-312.
17. Dahlin, D. C.; Miwa, G. T.; Lu, A. Y.; Nelson, S. D. N-acetyl-pbenzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. USA, 1984, 81, 1327-1331.
18. Bessems, J. G.; Vermeulen, N. P. Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit. Rev. Toxicol., 2001, 31, 55-138.
19. Argikar, U. A.; Remmel, R. P. Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDPglucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Drug Metab. Dispos., 2009, 37, 229-236.
20. Tang, W.; Abbott, F. S. Bioactivation of a toxic metabolite of valproic acid, (E)-2-propyl-2,4-pentadienoic acid, via glucuronidation. LC/MS/MS characterization of the GSH-glucuronide diconjugates. Chem. Res. Toxicol., 1996, 9, 517-526.
21. Sadeque, A. J.; Fisher, M. B.; Korzekwa, K. R.; Gonzalez, F. J.; Rettie, A. E. Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. J. Pharmacol. Exp. Ther., 1997, 283, 698-703.
22. Mutlib, A. E.; Gerson, R. J.; Meunier, P. C.; Haley, P. J.; Chen, H.; Gan, L. S.; Davies, M. H.; Gemzik, B.; Christ, D. D.; Krahn, D. F.; Markwalder, J. A.; Seitz, S. P.; Robertson, R. T.; Miwa, G. T. The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats. Toxicol. Appl. Pharmacol., 2000, 169, 102-113.
23. Argikar, U. A.; Remmel, R. P. Variation in glucuronidation of lamotrigine in human liver microsomes. Xenobiotica, 2009, 39, 355-363.
24. Argikar, U. A.; Senekeo-Effenberger, K.; Larson, E. E.; Tukey, R. H.; Remmel, R. P. Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica, 2009, 39, 826-835.
25. Remmel, R. P.; Coughtrie, M. W. H.; Zihnioglu, F.; Burchell, B. In: Studies on the N-glucuronidation of lamotrigine by human, guinea pig, and rabbit UDP-glucuronosyltransferases. 7th Int. Workshop on Glucuronidation and the UDPglucuronosyltransferases. Pitlochry, Scotland, 1993.
26. Lu, W.; Uetrecht, J. P. Possible bioactivation pathways of lamotrigine. Drug Metab. Dispos., 2007, 35, 1050-1056.
27. Maggs, J. L.; Naisbitt, D. J.; Tettey, J. N.; Pirmohamed, M.; Park, B. K. Metabolism of lamotrigine to a reactive arene oxide intermediate. Chem. Res. Toxicol., 2000, 13, 1075-1081.
28. Lee, W. M. Drug-induced hepatotoxicity. N. Engl. J. Med., 2003, 349, 474-485.
29. Miller, J. A.; Miller, E. C. The metabolism and carcinogenicity of p-dimethylaminoazobenzene and related compounds in the rat. Cancer Res., 1947, 7, 39-41.
30. Pirmohamed, M.; Madden, S.; Park, B. K. Idiosyncratic drug reactions. Metabolic bioactivation as a pathogenic mechanism. Clin.Pharmacokinet., 1996, 31, 215-230.
31. Prescott, L. F. Reactive metabolites as a cause of hepatotoxicity. Int. J. Clin. Pharmacol. Res., 1983, 3, 437-441.
32. Guengerich, F. P. Metabolic activation of carcinogens. Pharmacol. Ther., 1992, 54, 17-61.
33. Juchau, M. R.; Lee, Q. P.; Fantel, A. G. Xenobiotic biotransformation/bioactivation in organogenesis-stage conceptual tissues: implications for embryotoxicity and teratogenesis. Drug Metab. Rev., 1992, 24, 195-238.
34. Hess, D. A.; Rieder, M. J. The role of reactive drug metabolites in immune-mediated adverse drug reactions. Ann. Pharm., 1997, 31, 1378-1387.
35. Uetrecht, J. Bioactivation. In: Drug Metabolizing Enzymes, Lee, J. S.; Obach, R. S., Eds. Informa: Boca Raton, FL, 2003; p 577.
36. Guengerich, F. P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol., 2001, 14, 611-650.
37. Fisher, M. B.; Henne, K. R.; Boer, J. The complexities inherent in attempts to decrease drug clearance by blocking sites of CYPmediated metabolism. Curr. Opin. Drug Discov. Devel., 2006, 9, 101-109.
38. Njoku, D.; Laster, M. J.; Gong, D. H.; Eger, E. I. 2nd; Reed, G. F.; Martin, J. L. Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury. Anesth. Analg., 1997, 84, 173-178.
39. Ernest, C. S., 2nd; Hall, S. D.; Jones, D. R. Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J. Pharmacol. Exp. Ther., 2005, 312, 583-591.
40. Koudriakova, T.; Iatsimirskaia, E.; Utkin, I.; Gangl, E.; Vouros, P.; Storozhuk, E.; Orza, D.; Marinina, J.; Gerber, N. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochromeP4503A by ritonavir. Drug Metab. Dispos., 1998, 26, 552-561.
41. Gardner, I.; Popovic, M.; Zahid, N.; Uetrecht, J. P. A comparison of the covalent binding of clozapine, procainamide, and vesnarinoneto human neutrophils in vitro and rat tissues in vitro and in vivo. Chem. Res. Toxicol., 2005, 18, 1384-1394.
42. Mehvar, R.; Brocks, D. R.; Vakily, M. Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs. Clin. Pharmacokinet., 2002, 41, 533-558.
43. Roberts, P.; Kitteringham, N. R.; Park, B. K. Elucidation of the structural requirements for the bioactivation of mianserin in-vitro. J. Pharm. Pharmacol., 1993, 45, 663-665.
44. Erve, J. C.; Vashishtha, S. C.; DeMaio, W.; Talaat, R. E. Metabolism of prazosin in rat, dog, and human liver microsomes and cryopreserved rat and human hepatocytes and characterization of metabolites by liquid chromatography/tandem mass spectrometry. Drug Metab. Dispos., 2007, 35, 908-916.
45. Erve, J. C.; Vashishtha, S. C.; Ojewoye, O.; Adedoyin, A.; Espina, R.; Demaio, W.; Talaat, R. E. Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS). Xenobiotica, 2008, 38, 540-558.
46. Elliott, H. L.; Meredith, P. A.; Reid, J. L. Pharmacokinetic overview of doxazosin. Am. J. Cardiol., 1987, 59, 78G-81G.
47. Zhang, Z.; Chen, Q.; Li, Y.; Doss, G. A.; Dean, B. J.; Ngui, J. S.; Silva Elipe, M.; Kim, S.; Wu, J. Y.; Dininno, F.; Hammond, M. L.; Stearns, R. A.; Evans, D. C.; Baillie, T. A.; Tang, W. In vitro bioactivation of dihydrobenzoxathiin selective estrogen receptor modulators by cytochrome P450 3A4 in human liver microsomes: formation of reactive iminium and quinone type metabolites. Chem. Res. Toxicol., 2005, 18, 675-685.
48. Wen, B.; Ma, L.; Rodrigues, A. D.; Zhu, M. Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab. Dispos., 2008, 36, 841-850.
49. Kalgutkar, A. S.; Henne, K. R.; Lame, M. E.; Vaz, A. D.; Collin, C.; Soglia, J. R.; Zhao, S. X.; Hop, C. E., Metabolic activation ofthe nontricyclic antidepressant trazodone to electrophilic quinoneimineand epoxide intermediates in human liver microsomes and recombinant P4503A4. Chem. Biol. Interact., 2005, 155, 10-20.
50. Bauman, J. N.; Frederick, K. S.; Sawant, A.; Walsky, R. L.; Cox, L. M.; Obach, R. S.; Kalgutkar, A. S. Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug. Drug Metab. Dispos., 2008, 36, 1016-1029.
51. Qin, Z.; Kastrati, I.; Ashgodom, R. T.; Lantvit, D. D.; Overk, C. R.; Choi, Y.; van Breemen, R. B.; Bolton, J. L.; Thatcher, G. R. Structural modulation of oxidative metabolism in design of improved benzothiophene selective estrogen receptor modulators. Drug Metab. Dispos., 2009, 37, 161-169.
52. Uetrecht, J.; Zahid, N.; Tehim, A.; Fu, J. M.; Rakhit, S. Structural features associated with reactive metabolite formation in clozapine analogues. Chem. Biol. Interact., 1997, 104, 117-129.
53. Liegeois, J. F.; Bruhwyler, J.; Petit, C.; Damas, J.; Delarge, J.; Geczy, J.; Kauffmann, J. M.; Lamy, M.; Meltzer, H.; Mouithys-Mickalad, A. Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: application to antipsychotic drugs. Arch. Biochem. Biophys., 1999, 370, 126-137.
54. Hare, R. L.; Holcomb, B.; Page, O. C.; Stephens, J. W. Toxicity of carbutamide; report of a fatal case of bone-marrow depression and anuria. N. Engl. J. Med., 1957, 256, 74-76.
55. Tingle, M. D.; Jewell, H.; Maggs, J. L.; O'Neill, P. M.; Park, B. K. The bioactivation of amodiaquine by human polymorphonuclear leucocytes in vitro: chemical mechanisms and the effects of fluorine substitution. Biochem. Pharmacol., 1995, 50, 1113-1119.
56. Mizuno, K.; Katoh, M.; Okumura, H.; Nakagawa, N.; Negishi, T.; Hashizume, T.; Nakajima, M.; Yokoi, T. Metabolic activation of benzodiazepines by CYP3A4. Drug Metab. Dispos., 2009, 37, 345-351.
57. Chambers, R. J.; Marfat, A.; Antognoli, G. W.; Cheng, J. B.; Damon, D. B.; Kuperman, A. V.; Liston, T. C.; Mebus, C.; Pillar, J. S.; Shirley, J. T.; Watson, J. W. Discovery of CP-199,330 and CP-199,331: two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity. Bioorg. Med. Chem.Lett., 1999, 9, 2773-2778.
58. Woolf, T. F.; Pool, W. F.; Bjorge, S. M.; Chang, T.; Goel, O. P.; Purchase, C. F. 2nd; Schroeder, M. C.; Kunze, K. L.; Trager, W. F., Bioactivation and irreversible binding of the cognition activator tacrine using human and rat liver microsomal preparations. Species difference. Drug Metab. Dispos., 1993, 21, 874-882.
59. Madden, S.; Spaldin, V.; Hayes, R. N.; Woolf, T. F.; Pool, W. F.; Park, B. K. Species variation in the bioactivation of tacrine by hepatic microsomes. Xenobiotica, 1995, 25, 103-116.
60. Kalgutkar, A. S.; Griffith, D. A.; Ryder, T.; Sun, H.; Miao, Z.; Bauman, J. N.; Didiuk, M. T.; Frederick, K. S.; Zhao, S. X.; Prakash, C.; Soglia, J. R.; Bagley, S. W.; Bechle, B. M.; Kelley, R. M.; Dirico, K.; Zawistoski, M.; Li, J.; Oliver, R.; Guzman-Perez, A.; Liu, K. K.; Walker, D. P.; Benbow, J. W.; Morris, J. Discovery Tactics to mitigate toxicity risks due to reactive metabolite formation with 2-(2-Hydroxyaryl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives, potent calcium-sensing receptor antagonists and clinical candidate(s) for the treatment of osteoporosis. Chem. Res. Toxicol., 2010, 23, 1115-1126.
61. Castillo, M.; Lam, Y. W.; Dooley, M. A.; Stahl, E.; Smith, P. C. Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly. Clin. Pharmacol. Ther., 1995, 57, 636-644.
62. Castillo, M.; Smith, P. C. Disposition and reactivity of ibuprofen and ibufenac acyl glucuronides in vivo in the rhesus monkey and in vitro with human serum albumin. Drug. Metab. Dispos., 1995, 23, 566-572.
63. Benet, L. Z.; Spahn-Langguth, H.; Iwakawa, S.; Volland, C.; Mizuma, T.; Mayer, S.; Mutschler, E.; Lin, E. T. Predictability of the covalent binding of acidic drugs in man. Life Sci., 1993, 53, PL141-PL146.
64. Wang, J.; Davis, M.; Li, F.; Azam, F.; Scatina, J.; Talaat, R. A novel approach for predicting acyl glucuronide reactivity via Schiff base formation: development of rapidly formed peptide adducts for LC/MS/MS measurements. Chem. Res. Toxicol., 2004, 17, 1206-1216.
65. Kitani, M.; Miyamoto, G.; Nagasawa, M.; Yamada, T.; Matsubara, J.; Uchida, M.; Odomi, M. Biotransformation of the novel inotropic agent toborinone (OPC-18790) in rats and dogs. Evidence for the formation of novel glutathione and two cysteine conjugates. Drug Metab. Dispos., 1997, 25, 663-674.
66. Masubuchi, Y.; Igarashi, S.; Suzuki, T.; Horie, T.; Narimatsu, S. Imipramine-induced inactivation of a cytochrome P450 2D enzyme in rat liver microsomes: in relation to covalent binding of its reactive intermediate. J. Pharmacol. Exp. Ther., 1996, 279, 724-731.
67. Li, X.; He, Y.; Ruiz, C. H.; Koenig, M.; Cameron, M. D.; Vojkovsky, T. Characterization of dasatinib and its structural analogs as CYP3A4 mechanism-based inactivators and the proposed bioactivation pathways. Drug Metab. Dispos., 2009, 37, 1242-1250.
68. Hartz, R. A.; Ahuja, V. T.; Zhuo, X.; Mattson, R. J.; Denhart, D. J.; Deskus, J. A.; Vrudhula, V. M.; Pan, S.; Ditta, J. L.; Shu, Y. Z.; Grace, J. E.; Lentz, K. A.; Lelas, S.; Li, Y. W.; Molski, T. F.; Krishnananthan, S.; Wong, H.; Qian-Cutrone, J.; Schartman, R.; Denton, R.; Lodge, N. J.; Zaczek, R.; Macor, J. E.; Bronson, J. J. A strategy to minimize reactive metabolite formation: discovery of(S)-4-(1-cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2,5-dimethylpy ridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor antagonist. J. Med. Chem., 2009, 52, 7653-7668.
69. Smith, K. S.; Smith, P. L.; Heady, T. N.; Trugman, J. M.; Harman, W. D.; Macdonald, T. L. In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity. Chem. Res. Toxicol., 2003, 16, 123-128.
70. Jorga, K.; Fotteler, B.; Heizmann, P.; Gasser, R. Metabolism and excretion of tolcapone, a novel inhibitor of catechol-Omethyltransferase. Br. J. Clin. Pharmacol., 1999, 48, 513-520.
71. Wikberg, T.; Ottoila, P.; Taskinen, J. Identification of major urinary metabolites of the catechol-O-methyltransferase inhibitor entacapone in the dog. Eur. J. Drug Metab. Pharm., 1993, 18, 359-367.
72. Durand, A.; Thenot, J. P.; Bianchetti, G.; Morselli, P. L. Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem. Drug Metab. Rev., 1992, 24, 239-266.
73. Reist, M.; Roy-deVos, M.; Montseny, J. P.; Mayer, J. M.; Carrupt, P. A.; Berger, Y.; Testa, B. Very slow chiral inversion of clopi dogrel in rats: a pharmacokinetic and mechanistic investigation. Drug Metab. Dispos., 2000, 28, 1405-1410.
74. Dansette, P. M.; Libraire, J.; Bertho, G.; Mansuy, D. Metabolic oxidative cleavage of thioesters: evidence for the formation of sulfenic acid intermediates in the bioactivation of the antithrombotic prodrugs ticlopidine and clopidogrel. Chem. Res. Toxicol., 2009, 22, 369-373.
75. Chesne, C.; Guyomard, C.; Guillouzo, A.; Schmid, J.; Ludwig, E.; Sauter, T. Metabolism of meloxicam in human liver involves cytochromes P4502C9 and 3A4. Xenobiotica,1998, 28, 1-13.
76. Obach, R. S.; Kalgutkar, A. S.; Ryder, T. F.; Walker, G. S. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam. Chem. Res. Toxicol., 2008, 21, 1890-1899.
77. Woolf, T. F.; Radulovic, L. L. Oxicams: metabolic disposition in man and animals. Drug Metab. Rev., 1989, 21, 255-276.
78. Bell, J. A.; Dallas, F. A.; Jenner, W. N.; Martin, L. E. The metabolism of ranitidine in animals and man [proceedings]. Biochem. Soc. Trans., 1980, 8, 93.
79. Yeh, K. C.; Chremos, A. N.; Lin, J. H.; Constanzer, M. L.; Kanovsky, S. M.; Hucker, H. B.; Antonello, J.; Vlasses, P.; Ryan, J. R.; Williams, R. L. Single-dose pharmacokinetics and bioavailability of famotidine in man. Results of multicenter collaborative studies. Biopharm. Drug Dispos., 1987, 8, 549-560.
80. Kalgutkar, A. S.; Bauman, J. N.; McClure, K. F.; Aubrecht, J.; Cortina, S. R.; Paralkar, J. Biochemical basis for differences in metabolism-dependent genotoxicity by two diazinylpiperazine-based 5-HT2C receptor agonists. Bioorg. Med. Chem. Lett., 2009, 19, 1559-1563.
81. Kalgutkar, A. S.; Dalvie, D. K.; Aubrecht, J.; Smith, E. B.; Coffing, S. L.; Cheung, J. R.; Vage, C.; Lame, M. E.; Chiang, P.; McClure, K. F.; Maurer, T. S.; Coelho, R. V. Jr.; Soliman, V. F.; Schildknegt, K. Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl)pyrazine, a novel 5-hydroxytryptamine2c receptor agonist for the treatment of obesity: role of metabolic activation. Drug Metab. Dispos., 2007, 35, 848-858.
82. Cruciani, G.; Carosati, E.; De Boeck, B.; Ethirajulu, K.; Mackie, C.; Howe, T.; Vianello, R. MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J. Med. Chem., 2005, 48, 6970-6979.
83. Zientek, M.; Stoner, C.; Ayscue, R.; Klug-McLeod, J.; Jiang, Y.; West, M.; Collins, C.; Ekins, S. Integrated in silico-in vitro strategy for addressing cytochrome P450 3A4 time-dependent inhibition. Chem. Res. Toxicol., 2010, 23, 664-676.
84. Ma, S.; Zhu, M. Recent advances in applications of liquid chromatography-tandem mass spectrometry to the analysis of reactive drug metabolites. Chem. Biol. Interact, 2009, 179, 25-37.
85. Tang, W.; Lu, A. Y. Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective. Drug Metab. Rev., 2010, 42, 225-249.
86. Onoue, S.; Ochi, M.; Gandy, G.; Seto, Y.; Igarashi, N.; Yamauchi, Y.; Yamada, S. High-throughput screening system for identifying phototoxic potential of drug candidates based on derivatives of reactive oxygen metabolites. Pharm. Res., 2010, 27, 1610-1619.
87. Skonberg, C.; Olsen, J.; Madsen, K. G.; Hansen, S. H.; Grillo, M. P. Metabolic activation of carboxylic acids. Expert. Opin. Drug Metab. Toxicol., 2008, 4, 425-438.
88. Smith, P. C.; Benet, L. Z.; McDonagh, A. F. Covalent binding of zomepirac glucuronide to proteins: evidence for a Schiff basemechanism. Drug Metab. Dispos., 1990, 18, 639-644.
89. Smith, P. C.; Liu, J. H. Covalent binding of suprofen acyl glucuronide to albumin in vitro. Xenobiotica, 1993, 23, 337-348.
90. Ding, A.; Ojingwa, J. C.; McDonagh, A. F.; Burlingame, A. L.;Benet, L. Z. Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry. Proc. Natl. Acad. Sci. USA, 1993, 90, 3797-3801.
91. Li, C.; Benet, L. Z.; Grillo, M. P. Studies on the chemical reactivity of 2-phenylpropionic acid 1-O-acyl glucuronide and S-acyl-CoA thioester metabolites. Chem. Res. Toxicol., 2002, 15, 1309-1317.
92. Olsen, J.; Li, C.; Bjornsdottir, I.; Sidenius, U.; Hansen, S. H.; Benet, L. Z. In vitro and in vivo studies on acyl-coenzyme Adependent bioactivation of zomepirac in rats. Chem. Res. Toxicol., 2005, 18, 1729-1736.
93. Wen, B.; Coe, K. J.; Rademacher, P.; Fitch, W. L.; Monshouwer, M.; Nelson, S. D. Comparison of in vitro bioactivation of flutamide and its cyano analogue: Evidence for Reductive Activation by human NADPH:Cytochrome P450 reductase. Chem. Res. Toxicol., 2008, 21, 2393-2406.
94. Mannargudi, B.; McNally, D.; Reynolds, W.; Uetrecht, J. Bioactivationof minocycline to reactive intermediates by myeloperoxidase,horseradish peroxidase, and hepatic microsomes: implicationsfor minocycline-induced lupus and hepatitis. Drug Metab. Dispos.,2009, 37, 1806-1818.
95. Lai, W. G.; Gardner, I.; Zahid, N.; Uetrecht, J. P. Bioactivation and covalent binding of hydroxyfluperlapine in human neutrophils: implications for fluperlapine-induced agranulocytosis. Drug Metab.Dispos., 2000, 28, 255-263.
96. Tang, W. Drug metabolite profiling and elucidation of druginduced hepatotoxicity. Expert. Opin. Drug Metab. Toxicol., 2007, 3, 407-420.
97. Ramirez-Molina, C.; Burton, L. Screening strategy for the rapiddetection of in vitro generated glutathione conjugates using highperformanceliquid chromatography and low-resolution mass spectrometryin combination with Light Sight software for data processing. Rapid Commun. Mass Spectrom., 2009, 23, 3501-3512.
98. Argoti, D.; Liang, L.; Conteh, A.; Chen, L.; Bershas, D.; Yu, C. P.; Vouros, P.; Yang, E. Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chem. Res. Toxicol., 2005, 18, 1537-1544.
99. Yang, X.; Chen, W. In vitro microsomal metabolic studies on a selective mGluR5 antagonist MTEP: characterization of in vitro metabolites and identification of a novel thiazole ring opening aldehyde metabolite. Xenobiotica, 2005, 35, 797-809.
100. Sahali-Sahly, Y.; Balani, S. K.; Lin, J. H.; Baillie, T. A. In vitro studies on the metabolic activation of the furanopyridine L-754,394, a highly potent and selective mechanism-based inhibitor of cytochrome P450 3A4. Chem. Res. Toxicol., 1996, 9, 1007-1012.
101. Baillie, T. A.; Davis, M. R. Mass spectrometry in the analysis of glutathione conjugates. Biol. Mass Spectrom, 1993, 22, 319-325.
102. Dieckhaus, C. M.; Fernandez-Metzler, C. L.; King, R.; Krolikowski, P. H.; Baillie, T. A. Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem. Res. Toxicol., 2005, 18, 630-638.
103. Zhang, D.; Zhang, H.; Aranibar, N.; Hanson, R.; Huang, Y.; Cheng, P. T.; Wu, S.; Bonacorsi, S.; Zhu, M.; Swaminathan, A.; Humphreys, W. G. Structural elucidation of human oxidative metabolites of muraglitazar: use of microbial bioreactors in the biosynthesis of metabolite standards. Drug Metab. Dispos., 2006, 34, 267-280.
104. Gan, J.; Harper, T. W.; Hsueh, M. M.; Qu, Q.; Humphreys, W. G. Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem. Res. Toxicol., 2005, 18, 896-903.
105. Gan, J.; Ruan, Q.; He, B.; Zhu, M.; Shyu, W. C.; Humphreys, W. G. In vitro screening of 50 highly prescribed drugs for thiol adductformation--comparison of potential for drug-induced toxicity and extent of adduct formation. Chem. Res. Toxicol., 2009, 22, 690-698.
106. Soglia, J. R.; Harriman, S. P.; Zhao, S.; Barberia, J.; Cole, M. J.; Boyd, J. G.; 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., 2004, 36, 105-116.
107. Mutlib, A. E. Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Chem. Res. Toxicol., 2008, 21, 1672-1689.
108. Meneses-Lorente, G.; Sakatis, M. Z.; Schulz-Utermoehl, T.; De Nardi, C.; Watt, A. P. A quantitative high-throughput trapping assayas a measurement of potential for bioactivation. Anal. Biochem., 2006, 351, 266-272.
109. Masubuchi, N.; Makino, C.; Murayama, N. Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans. Chem. Res. Toxicol., 2007, 20, 455-464.
110. Fisher, M. B.; Campanale, K.; Ackermann, B. L.; VandenBranden, M.; Wrighton, S. A. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab.Dispos., 2000, 28, 560-566.
111. Seitz, S.; Kretz-Rommel, A.; Oude Elferink, R. P.; Boelsterli, U. A. Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2). Chem. Res. Toxicol., 1998, 11, 513-519.
112. Nakayama, S.; Atsumi, R.; Takakusa, H.; Kobayashi, Y.; Kurihara, A.; Nagai, Y.; Nakai, D.; Okazaki, O. A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding. Drug Metab. Dispos., 2009, 37, 1970-1977.
113. Takakusa, H.; Masumoto, H.; Yukinaga, H.; Makino, C.; Nakayama, S.; Okazaki, O.; Sudo, K. Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab. Dispos., 2008, 36, 1770-1779.
114. Usui, T.; Mise, M.; Hashizume, T.; Yabuki, M.; Komuro, S. Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. Drug Metab. Dispos., 2009, 37, 2383-2392.
115. Cohen, S. D.; Pumford, N. R.; Khairallah, E. A.; Boekelheide, K.; Pohl, L. R.; Amouzadeh, H. R.; Hinson, J. A. Selective protein covalent binding and target organ toxicity. Toxicol. Appl. Pharmacol., 1997, 143, 1-12.
116. Shen, S.; Marchick, M. R.; Davis, M. R.; Doss, G. A.; Pohl, L. R. Metabolic activation of diclofenac by human cytochrome P450 3A4: role of 5-hydroxydiclofenac. Chem. Res. Toxicol., 1999, 12, 214-222.
117. Liebler, D. C. Protein damage by reactive electrophiles: targets and consequences. Chem. Res. Toxicol., 2008, 21, 117-128.
118. Day, S. H.; Mao, A.; White, R.; Schulz-Utermoehl, T.; Miller, R.; Beconi, M. G. A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J. Pharmacol. Toxicol. Methods, 2005, 52, 278-285.
119. Cribb, A. E.; Lee, B. L.; Trepanier, L. A.; Spielberg, S. P. Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis. Adverse Drug ReactToxicol. Rev., 1996, 15, 9-50.
120. Cribb, A. E.; Pohl, L. R.; Spielberg, S. P.; Leeder, J. S. Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins. J. Pharmacol. Exp. Ther., 1997, 282, 1064-1071.
121. Keisu, M.; Anderson, T. B. Drug-induced liver injury in humans: the case of ximelagatran. In: Adverse Drug Reactions, Uetrecht, J., Ed. Springer-Verlag: Berlin, Heidelberg, 2010; Vol. 196, pp. 407-418.
122. Garnock-Jones, K. P.; Keating, G. M.; Scott, L. J. Trastuzumab: A review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Drugs, 2010, 70, 215-239.