Structural Alerts for Toxicity

This chapter summarizes structural alerts where there is a significant weight of evidence that their incorporation into a drug candidate molecule is likely to result in a higher than average incidence of attrition due to adverse safety/or toxicity findings. The mechanism of formation of reactive metabolites from each structural alert is summarized. The structure–toxicity relationships and the boundary of definition for each structural alert are discussed. The benefits of low exposure and alternative routes of metabolism are highlighted along with screening methods to manage the risks associated with structural alerts. Keywords: CYP inhibition; idiosyncratic toxicity; reactive metabolite; structural alert; toxicophore

[1]  M. Foppiano,et al.  Worldwide pharmacovigilance systems and tolrestat withdrawal , 1997, The Lancet.

[2]  T. Mizutani,et al.  Evidence for the involvement of N-methylthiourea, a ring cleavage metabolite, in the hepatotoxicity of methimazole in glutathione-depleted mice: structure-toxicity and metabolic studies. , 2000, Chemical research in toxicology.

[3]  C. Scott,et al.  The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. , 2006, Cancer cell.

[4]  M. Salemi,et al.  Characterization of a structurally intact in situ lung model and comparison of naphthalene protein adducts generated in this model vs lung microsomes. , 2005, Chemical research in toxicology.

[5]  S. Wrighton,et al.  The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. , 2002, British journal of clinical pharmacology.

[6]  P. Eyer,et al.  Formation and disposition of nitrosochloramphenicol in rat liver. , 1985, Biochemical pharmacology.

[7]  J. Dearden,et al.  Structural basis for the haemotoxicity of dapsone: the importance of the sulphonyl group. , 1997, Toxicology.

[8]  M. Famulok,et al.  Formation of N‐(Deoxyguanosin‐8‐yl)aniline in the in vitro Reaction of N‐Acetoxyaniline with Deoxyguanosine and DNA , 1989 .

[9]  U. Boelsterli.  Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions. , 2002, Current drug metabolism.

[10]  J. Cravedi,et al.  Chloramphenicol oxamylethanolamine as an end product of chloramphenicol metabolism in rat and humans: evidence for the formation of a phospholipid adduct. , 1995, Chemical research in toxicology.

[11]  C. Sawyers,et al.  Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). , 2010, Journal of medicinal chemistry.

[12]  J. Reid,et al.  Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  David Lerner,et al.  Hydroxy-1-aminoindans and derivatives: preparation, stability, and reactivity. , 2006, The Journal of organic chemistry.

[14]  J. Miners,et al.  An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid. , 2006, British journal of clinical pharmacology.

[15]  T. Macdonald,et al.  Mechanisms of trovafloxacin hepatotoxicity: studies of a model cyclopropylamine-containing system. , 2007, Bioorganic & medicinal chemistry letters.

[16]  Jinping Gan,et al.  Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. , 2005, Chemical research in toxicology.

[17]  Y. Masubuchi,et al.  Mechanism-based inactivation of cytochrome P450s 1A2 and 3A4 by dihydralazine in human liver microsomes. , 1999, Chemical research in toxicology.

[18]  E A Emini,et al.  Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors. , 2000, Journal of medicinal chemistry.

[19]  Catrin Hasselgren,et al.  Explanation for main features of structure-genotoxicity relationships of aromatic amines by theoretical studies of their activation pathways in CYP1A2. , 2011, Journal of the American Chemical Society.

[20]  Laura P James,et al.  Acetaminophen‐Induced Hepatotoxicity: Role of Metabolic Activation, Reactive Oxygen/Nitrogen Species, and Mitochondrial Permeability Transition , 2004, Drug metabolism reviews.

[21]  K. Wallace.  Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis , 2007, Cardiovascular Toxicology.

[22]  N. Davies,et al.  Formation of reactive metabolites of phenacetin in humans and rats. , 1985, Xenobiotica; the fate of foreign compounds in biological systems.

[23]  K. Rhodes,et al.  Overcoming the genotoxicity of a pyrrolidine substituted arylindenopyrimidine as a potent dual adenosine A(2A)/A(1) antagonist by minimizing bioactivation to an iminium ion reactive intermediate. , 2011, Chemical research in toxicology.

[24]  Paul J Hergenrother,et al.  DNA as a target for anticancer compounds: methods to determine the mode of binding and the mechanism of action. , 2007, Current opinion in biotechnology.

[25]  E. Chan,et al.  Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib , 2010, Molecular Pharmacology.

[26]  J. Bauman,et al.  Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug , 2008, Drug Metabolism and Disposition.

[27]  M. Pirmohamed,et al.  Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo. , 2001, Chemical research in toxicology.

[28]  A. Stepan,et al.  Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. , 2011, Chemical research in toxicology.

[29]  J. Timbrell.  The role of metabolism in the hepatotoxicity of isoniazid and iproniazid. , 1979, Drug metabolism reviews.

[30]  J. Bolton,et al.  Bioactivation of tamoxifen to metabolite E quinone methide: reaction with glutathione and DNA. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[31]  E. Padovan,et al.  Molecular features of penicillin allergy. , 1998, The Journal of investigative dermatology.

[32]  J. C. Emmett,et al.  Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. , 1977, Journal of medicinal chemistry.

[33]  A. Kalgutkar,et al.  Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity? , 2009, Chemistry & biodiversity.

[34]  K. Beaumont,et al.  Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide: synthesis, reactivity, and mechanistic analysis. , 2007, Journal of medicinal chemistry.

[35]  M. Murray,et al.  Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. , 2000, Current drug metabolism.

[36]  Raffaella Corvi,et al.  How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop. , 2007, Mutation research.

[37]  R. Versace,et al.  In vitro metabolism of N-(5-chloro-2-methylphenyl)-N'-(2-methylpropyl)thiourea: species comparison and identification of a novel thiocarbamide-glutathione adduct. , 1997, Chemical research in toxicology.

[38]  P. Dansette,et al.  Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. , 2005, Current drug metabolism.

[39]  M. Isobe,et al.  Metabolic activation of the potent mutagen, 2-naphthohydroxamic acid, in Salmonella typhimurium TA98. , 1990, Cancer research.

[40]  D. Mansuy,et al.  Thiophene S-oxides as new reactive metabolites: formation by cytochrome P-450 dependent oxidation and reaction with nucleophiles , 1991 .

[41]  S. Alexson,et al.  Involvement of liver carboxylesterases in the in vitro metabolism of lidocaine. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[42]  A. Cho,et al.  Comparative studies of N-hydroxylation and N-demethylation by microsomal cytochrome P-450. , 1991, Chemical research in toxicology.

[43]  P. G. Wells,et al.  Phenytoin covalent binding and embryopathy in mouse embryos co-cultured with maternal hepatocytes from mouse, rat, and rabbit. , 1995, Biochemical pharmacology.

[44]  R Serafimova,et al.  Identification of the structural requirements for mutagencitiy, by incorporating molecular flexibility and metabolic activation of chemicals. II. General Ames mutagenicity model. , 2007, Chemical research in toxicology.

[45]  Lue Ping Zhao,et al.  Phenotypic anchoring of global gene expression profiles induced by N-hydroxy-4-acetylaminobiphenyl and benzo[a]pyrene diol epoxide reveals correlations between expression profiles and mechanism of toxicity. , 2005, Chemical research in toxicology.

[46]  J. Peterson.  The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. , 2006, Cardiovascular research.

[47]  P. Klöhn,et al.  A metabolite of carcinogenic 2-acetylaminofluorene, 2-nitrosofluorene, induces redox cycling in mitochondria. , 1995, Biochimica et biophysica acta.

[48]  P. Ortiz de Montellano,et al.  Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases. , 2011, Chemico-biological interactions.

[49]  D. Mansuy,et al.  Thiophene sulfoxides as reactive metabolites: formation upon microsomal oxidation of a 3-aroylthiophene and fate in the presence of nucleophiles in vitro and in vivo. , 1996, Chemical research in toxicology.

[50]  C. W. von der Lieth,et al.  The structural basis for the mutagenicity of aristolochic acid. , 1990, Cancer letters.

[51]  A. Antunes,et al.  Reactive aldehyde metabolites from the anti-HIV drug abacavir: amino acid adducts as possible factors in abacavir toxicity. , 2011, Chemical research in toxicology.

[52]  Chun Meng Song,et al.  Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1 , 2011 .

[53]  Peter D. Senter,et al.  Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[54]  F. Debellé,et al.  Aristolochic acid nephropathy: a worldwide problem. , 2008, Kidney international.

[55]  J. Kazius,et al.  Derivation and validation of toxicophores for mutagenicity prediction. , 2005, Journal of medicinal chemistry.

[56]  P. Hollenberg,et al.  Mechanism-based inactivation of cytochrome P450 3A4 by 17 alpha-ethynylestradiol: evidence for heme destruction and covalent binding to protein. , 2002, The Journal of pharmacology and experimental therapeutics.

[57]  G. Baker,et al.  Effects of the antidepressant/antipanic drug phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular gamma-aminobutyric acid levels in the striatum. , 2002, Biochemical pharmacology.

[58]  J. Baell,et al.  New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. , 2010, Journal of medicinal chemistry.

[59]  U. Busch,et al.  Meloxicam: metabolic profile and biotransformation products in the rat. , 1995, Xenobiotica; the fate of foreign compounds in biological systems.

[60]  R Scott Obach,et al.  Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. , 2008, Chemical research in toxicology.

[61]  P. Murphy,et al.  Biological inactivation of pyrrolnitrin. Identification and synthesis of pyrrolnitrin metabolites. , 1972, Journal of medicinal chemistry.

[62]  Gildas Bertho,et al.  First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives. , 2005, Biochemical and biophysical research communications.

[63]  Ronald D Snyder,et al.  DNA intercalative potential of marketed drugs testing positive in in vitro cytogenetics assays. , 2006, Mutation research.

[64]  P. Vereerstraeten,et al.  Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi) , 2000, The New England journal of medicine.

[65]  P. Scherle,et al.  Both 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones and 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones are light-dependent tumor necrosis factor-alpha antagonists. , 2003, Bioorganic & medicinal chemistry letters.

[66]  E. Fiala,et al.  N2-amination of guanine to 2-hydrazinohypoxanthine, a novel in vivo nucleic acid modification produced by the hepatocarcinogen 2-nitropropane. , 1998, Chemical research in toxicology.

[67]  Ernesto Callegari,et al.  A comprehensive listing of bioactivation pathways of organic functional groups. , 2005, Current drug metabolism.

[68]  Erin E. Carlson,et al.  Chemical probes of UDP-galactopyranose mutase. , 2006, Chemistry & biology.

[69]  David C Evans,et al.  EVIDENCE FOR THE BIOACTIVATION OF ZOMEPIRAC AND TOLMETIN BY AN OXIDATIVE PATHWAY: IDENTIFICATION OF GLUTATHIONE ADDUCTS IN VITRO IN HUMAN LIVER MICROSOMES AND IN VIVO IN RATS , 2006, Drug Metabolism and Disposition.

[70]  T. Baillie,et al.  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. , 2001, Chemical research in toxicology.

[71]  [3H]chloramphenicol metabolism in human volunteer: oxamic acid as a new major metabolite. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[72]  K. Koch,et al.  Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity , 2012, Drug Metabolism and Disposition.

[73]  C. Yuan,et al.  Detection and characterization of DNA adducts of 3-methylindole. , 2001, Chemical research in toxicology.

[74]  T. Macdonald,et al.  In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity. , 2003, Chemical research in toxicology.

[75]  J. Alleva.  METABOLISM OF TRANYLEYPROMINE-C14 AND DL AMPHETAMINE-C14 IN THE RAT. , 1963, Journal of medicinal chemistry.

[76]  P. Carrupt,et al.  The MPTP story: MAO activates tetrahydropyridine derivatives to toxins causing parkinsonism. , 1990, Drug metabolism reviews.

[77]  N. Masubuchi,et al.  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. , 2007, Chemical research in toxicology.

[78]  E. Fiala,et al.  Activation of the liver carcinogen 2-nitropropane by aryl sulfotransferase. , 1994, Chemical research in toxicology.

[79]  J. Bolton,et al.  4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. , 2000, Chemical research in toxicology.

[80]  A. Kalgutkar,et al.  Importance of Early Assessment of Bioactivation in Drug Discovery , 2006 .

[81]  F. Azam,et al.  A novel approach for predicting acyl glucuronide reactivity via Schiff base formation: development of rapidly formed peptide adducts for LC/MS/MS measurements. , 2004, Chemical research in toxicology.

[82]  J. Gillespie,et al.  Effect of Tadalafil on Cytochrome P450 3A4–mediated Clearance: Studies in Vitro and in Vivo , 2005, Clinical pharmacology and therapeutics.

[83]  T. Baillie,et al.  Zafirlukast Metabolism by Cytochrome P450 3A4 Produces an Electrophilic α,β-Unsaturated Iminium Species That Results in the Selective Mechanism-Based Inactivation of the Enzyme , 2005 .

[84]  Laura P James,et al.  Acetaminophen-induced hepatotoxicity. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[85]  R. J. Riley,et al.  Development of a Generalized, Quantitative Physicochemical Model of CYP3A4 Inhibition for Use in Early Drug Discovery , 2001, Pharmaceutical Research.

[86]  R. Obach,et al.  METABOLISM OF NOMIFENSINE TO A DIHYDROISOQUINOLINIUM ION METABOLITE BY HUMAN MYELOPEROXIDASE, HEMOGLOBIN, MONOAMINE OXIDASE A, AND CYTOCHROME P450 ENZYMES , 2006, Drug Metabolism and Disposition.

[87]  E. Gillam,et al.  Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[88]  Y. Masubuchi.  Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. , 2006, Drug metabolism and pharmacokinetics.

[89]  R. Zeldin,et al.  Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. , 2003, The Journal of antimicrobial chemotherapy.

[90]  Liang-Shang Gan,et al.  Bioactivation of benzylamine to reactive intermediates in rodents: formation of glutathione, glutamate, and peptide conjugates. , 2002, Chemical research in toxicology.

[91]  B. Peng,et al.  Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects , 2011, Drug Metabolism and Disposition.

[92]  C. D. Thompson,et al.  Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate. , 1996, Chemical research in toxicology.

[93]  C. Serabjit-Singh,et al.  Investigations of Hydrazine Cleavage of Eltrombopag in Humans , 2011, Drug Metabolism and Disposition.

[94]  Dean G. Brown,et al.  In Vitro Metabolism Studies of Nomifensine Monooxygenation Pathways: Metabolite Identification, Reaction Phenotyping, and Bioactivation Mechanism , 2010, Drug Metabolism and Disposition.

[95]  A. Mutlib,et al.  P450-mediated metabolism of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)- [1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole- 5-carboxamide (DPC 423) and its analogues to aldoximes. Characterization of glutathione conjugates of postulated intermediates derived from aldoximes. , 2002, Chemical research in toxicology.

[96]  J. Bauman,et al.  Toxicophores, reactive metabolites and drug safety: when is it a cause for concern? , 2008, Expert review of clinical pharmacology.

[97]  Ruth H. Hughes,et al.  Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials. , 2003, Journal of medicinal chemistry.

[98]  W. Bodell,et al.  Detection of DNA adducts in HL-60 cells treated with hydroquinone and p-benzoquinone by 32P-postlabeling. , 1991, Carcinogenesis.

[99]  W. Trager,et al.  Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. , 1998, Chemical research in toxicology.

[100]  D. Mansuy,et al.  Opposite behaviors of reactive metabolites of tienilic acid and its isomer toward liver proteins: use of specific anti-tienilic acid-protein adduct antibodies and the possible relationship with different hepatotoxic effects of the two compounds. , 1999, Chemical research in toxicology.

[101]  D. Mansuy,et al.  Hydroxylation of the thiophene ring by hepatic monooxygenases. Evidence for 5-hydroxylation of 2-aroylthiophenes as a general metabolic pathway using a simple UV-visible assay. , 1990, Biochemical pharmacology.

[102]  A. Breckenridge,et al.  Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV‐infected patients , 1997, AIDS.

[103]  B. K. Park,et al.  The bioactivation of amodiaquine by human polymorphonuclear leucocytes in vitro: chemical mechanisms and the effects of fluorine substitution. , 1995, Biochemical pharmacology.

[104]  M. Svensson,et al.  Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils. , 2004, Chemical research in toxicology.

[105]  Saurabh Aggarwal,et al.  An overview on 5α-reductase inhibitors , 2010, Steroids.

[106]  E. Furth,et al.  Mutagenicity of hydroxamic acids and the probable involvement of carbamoylation. , 1980, Cancer research.

[107]  D. Mansuy,et al.  Metabolic oxidative cleavage of thioesters: evidence for the formation of sulfenic acid intermediates in the bioactivation of the antithrombotic prodrugs ticlopidine and clopidogrel. , 2009, Chemical research in toxicology.

[108]  Julian Blagg,et al.  The Metabolism and Toxicity of Furosemide in the Wistar Rat and CD-1 Mouse: a Chemical and Biochemical Definition of the Toxicophore , 2007, Journal of Pharmacology and Experimental Therapeutics.

[109]  A. Basu,et al.  Mutagenicity of nitroaromatic compounds. , 2000, Chemical research in toxicology.

[110]  T. Baillie,et al.  Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. , 2004, Chemical research in toxicology.

[111]  A. Kalgutkar,et al.  Minimising the potential for metabolic activation in drug discovery , 2005, Expert opinion on drug metabolism & toxicology.

[112]  T. Twomey,et al.  Metabolism of sudoxicam by the rat, dog, and monkey. , 1977, Drug metabolism and disposition: the biological fate of chemicals.

[113]  K Beaumont,et al.  In vitro toxicity of zamifenacin (UK-76,654) and metabolites in primary hepatocyte cultures. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[114]  T. Mitchison,et al.  Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL , 2001, Nature Cell Biology.

[115]  E. Lipczynska-Kochany,et al.  Mutagenicity of pyridine- and quinoline-carbohydroxamic acid derivatives. , 1984, Mutation research.

[116]  D. Morris,et al.  Peptide-based in vitro assay for the detection of reactive metabolites. , 2008, Chemical research in toxicology.

[117]  S. Nelson,et al.  Metabolic activation and drug toxicity. , 1982, Journal of medicinal chemistry.

[118]  P. Murumkar,et al.  Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists--a perspective. , 2010, Bioorganic & medicinal chemistry.

[119]  A. Kalgutkar,et al.  NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. , 2007, Chemical research in toxicology.

[120]  D. Greenblatt,et al.  Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[121]  D. Underwood,et al.  Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[122]  T. Macdonald,et al.  In vitro metabolism of a model cyclopropylamine to reactive intermediate: insights into trovafloxacin-induced hepatotoxicity. , 2008, Chemical research in toxicology.

[123]  A. Zitting,et al.  Acute effects of 2-nitropropane on rat liver and brain. , 1981, Toxicology letters.

[124]  D. Doerge,et al.  Mechanism for the anti-thyroid action of minocycline. , 1997, Chemical research in toxicology.

[125]  T. Ikeda.  Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case. , 2011, Drug metabolism and pharmacokinetics.

[126]  B. Schmidt,et al.  Angiotensin II AT1 receptor antagonists. Clinical implications of active metabolites. , 2003, Journal of medicinal chemistry.

[127]  P. G. Wells,et al.  Free Radical Intermediates of Phenytoin and Related Teratogens , 1998, The Journal of Biological Chemistry.

[128]  D. Smith,et al.  Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[129]  Leonard Buckbinder,et al.  Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation. , 2008, Bioorganic & medicinal chemistry letters.

[130]  T. Monks,et al.  The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers. , 2002, Current drug metabolism.

[131]  R. Codd.  Traversing the coordination chemistry and chemical biology of hydroxamic acids , 2008 .

[132]  M. Miller,et al.  Identification of a carboxylesterase as the major protein bound by molinate. , 1998, Toxicology and applied pharmacology.

[133]  G. S. Walker,et al.  A rational chemical intervention strategy to circumvent bioactivation liabilities associated with a nonpeptidyl thrombopoietin receptor agonist containing a 2-amino-4-arylthiazole motif. , 2007, Chemical research in toxicology.

[134]  Dominic P. Williams,et al.  Adverse drug reactions, transcription factors and transcriptomics , 2003, Comparative Clinical Pathology.

[135]  M. Albassam,et al.  Subchronic Toxicity of Atorvastatin, a Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor, in Beagle Dogs , 1996, Toxicologic pathology.

[136]  M. Scheinin,et al.  Phenoxybenzamine Binding Reveals the Helical Orientation of the Third Transmembrane Domain of Adrenergic Receptors* , 2001, The Journal of Biological Chemistry.

[137]  M. Bailey,et al.  Acyl glucuronide reactivity in perspective: biological consequences. , 2003, Chemico-biological interactions.

[138]  R. Myers,et al.  Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride:  Enzyme-Catalyzed Formation of NADP−Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor , 1996 .

[139]  K. Ikehata,et al.  Covalent modification of microsomal lipids by thiobenzamide metabolites in vivo. , 2007, Chemical research in toxicology.

[140]  G. Yost,et al.  Evidence supporting the formation of 2,3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole. , 1998, Chemical Research in Toxicology.

[141]  G. Tarzia,et al.  Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine. III: Studies with the 13C-labelled drug. , 1987, Xenobiotica; the fate of foreign compounds in biological systems.

[142]  I. Mahmood,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Buspirone, an Anxiolytic Drug , 1999, Clinical pharmacokinetics.

[143]  G. Talaska,et al.  Smoking related carcinogen-DNA adducts in biopsy samples of human urinary bladder: identification of N-(deoxyguanosin-8-yl)-4-aminobiphenyl as a major adduct. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[144]  A. Kalgutkar,et al.  Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. , 2007, Current drug metabolism.

[145]  D. Mansuy,et al.  Chemical and Biological Oxidation of Thiophene: Preparation and Complete Characterization of Thiophene S-Oxide Dimers and Evidence for Thiophene S-Oxide as an Intermediate in Thiophene Metabolism in Vivo and in Vitro , 1997 .

[146]  N. Castagnoli,et al.  Metabolism of haloperidol and its tetrahydropyridine dehydration product HPTP. , 1998, Drug metabolism reviews.

[147]  A. Kalgutkar,et al.  A semiquantitative method for the determination of reactive metabolite conjugate levels in vitro utilizing liquid chromatography-tandem mass spectrometry and novel quaternary ammonium glutathione analogues. , 2006, Chemical research in toxicology.

[148]  J. Uetrecht,et al.  New concepts in immunology relevant to idiosyncratic drug reactions: the "danger hypothesis" and innate immune system. , 1999, Chemical research in toxicology.

[149]  Yi Li,et al.  Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening. , 2009, Bioorganic & Medicinal Chemistry Letters.

[150]  G. Tucker,et al.  The Consequences of 3,4-Methylenedioxymethamphetamine Induced CYP2D6 Inhibition in Humans , 2008, Journal of clinical psychopharmacology.

[151]  J. Radomski,et al.  Synergism among oral carcinogens: I. Results of the simultaneous feeding of four tumorigens to rats , 1965 .

[152]  J. Stephens,et al.  Toxicity of carbutamide; report of a fatal case of bone-marrow depression and anuria. , 1957, The New England journal of medicine.

[153]  G. Tarzia,et al.  Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog. , 1985, Xenobiotica; the fate of foreign compounds in biological systems.

[154]  R. Rodebaugh,et al.  Disposition and metabolism of prinomide in laboratory animals. , 1988, Drug metabolism and disposition: the biological fate of chemicals.

[155]  J. Alpert,et al.  Chemistry, Pharmacology, Antiarrhythmic Efficacy and Adverse Effects of Tocainide Hydrochloride, An Orally Active Structural Analog of Lidocaine , 1983, Pharmacotherapy.

[156]  F. Jamali,et al.  Clinical Pharmacokinetics of Ketorolac Tromethamine , 1992, Clinical pharmacokinetics.

[157]  A. Kalgutkar,et al.  Can in vitro metabolism-dependent covalent binding data distinguish hepatotoxic from nonhepatotoxic drugs? An analysis using human hepatocytes and liver S-9 fraction. , 2009, Chemical research in toxicology.

[158]  Thomas Sander,et al.  Toxicity-Indicating Structural Patterns , 2006, J. Chem. Inf. Model..

[159]  D. Mansuy.  Molecular structure and hepatotoxicity: compared data about two closely related thiophene compounds. , 1997, Journal of hepatology.

[160]  R Scott Obach,et al.  In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam. , 2008, Chemical research in toxicology.

[161]  John C Lindon,et al.  Acyl glucuronides: biological activity, chemical reactivity, and chemical synthesis. , 2006, Journal of medicinal chemistry.

[162]  R. Turesky.  HETEROCYCLIC AROMATIC AMINE METABOLISM, DNA ADDUCT FORMATION, MUTAGENESIS, AND CARCINOGENESIS , 2002, Drug metabolism reviews.

[163]  S. Rokita,et al.  Substituents on quinone methides strongly modulate formation and stability of their nucleophilic adducts. , 2006, Journal of the American Chemical Society.

[164]  A. Yunis,et al.  Chloramphenicol: relation of structure to activity and toxicity. , 1988, Annual review of pharmacology and toxicology.

[165]  E. Chan,et al.  Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib , 2011, Drug Metabolism and Disposition.

[166]  M. Chordia,et al.  In vitro nimesulide studies toward understanding idiosyncratic hepatotoxicity: diiminoquinone formation and conjugation. , 2009, Chemical research in toxicology.

[167]  A. D. Rodrigues,et al.  Screening of drug candidates for their drug--drug interaction potential. , 2001, Current opinion in chemical biology.

[168]  J. Uetrecht,et al.  Oxidation of diclofenac to reactive intermediates by neutrophils, myeloperoxidase, and hypochlorous acid. , 1997, Chemical research in toxicology.

[169]  F. Beland,et al.  Effect of substitution site upon the oxidation potentials of alkylanilines, the mutagenicities of N-hydroxyalkylanilines, and the conformations of alkylaniline-DNA adducts. , 1997, Chemical research in toxicology.

[170]  Ernesto Estrada,et al.  Automatic extraction of structural alerts for predicting chromosome aberrations of organic compounds. , 2006, Journal of molecular graphics & modelling.