Role of Bioactivation in Idiosyncratic Drug Toxicity: Structure–Toxicity Relationships

I have always been interested in chemistry and biology. My undergraduate, graduate,and postdoctoral trainings in pharmacy, medicinal chemistry and pharmacology,respectively, have strengthened this interest and led me to realize that significantadvances in medicine have frequently been realized because of research at the chemis-try–biology interface. I am hoping that this comprehensive volume on recent advancesin bioactivation research will stimulate pharmacologists, medicinal chemists, pharma-ceutical scientists, and graduate students in these fields and related areas to consider anduse bioactivation research when they explore and chart new frontiers in drug design anddrug development and when they consider ways to reduce the side effects of existingdrugs by making prodrugs. As for the toxicologists and environmental health scientists, Ihope this volume will help them generate the knowledge needed to understand bettermechanisms of toxicity to improve human risk assessments and intervention methodsafter occupational or environmental exposure to various hazardous chemicals.Adnan A. Elfarra, Ph.D.vii

[1]  N. Pumford,et al.  Protein targets of xenobiotic reactive intermediates. , 1997, Annual review of pharmacology and toxicology.

[2]  S. Dworetzky,et al.  Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition. , 2003, Journal of medicinal chemistry.

[3]  T. Baillie,et al.  Mass spectrometry in the analysis of glutathione conjugates. , 1993, Biological mass spectrometry.

[4]  J. Madrenas,et al.  Cytotoxicity of sulfonamide reactive metabolites: apoptosis and selective toxicity of CD8+ cells by the hydroxylamine of sulfamethoxazole , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  J. Taskinen,et al.  Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in rats and humans. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[6]  R. Boulieu,et al.  Development of an in vitro screening model for the biosynthesis of acyl glucuronide metabolites and the assessment of their reactivity toward human serum albumin. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[7]  J. Uetrecht,et al.  A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. , 1998, Molecular pharmacology.

[8]  R. Andrade,et al.  Drug-induced hepatotoxicity , 2003, The New England journal of medicine.

[9]  H. Meltzer,et al.  Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: application to antipsychotic drugs. , 1999, Archives of biochemistry and biophysics.

[10]  H.,et al.  Cytochrome P-450-catalyzed Hydroxylation and Carboxylic Acid Ester Cleavage of Hantzsch Pyridine Esters * , 2001 .

[11]  D. Pessayre,et al.  Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. , 2001, The Journal of pharmacology and experimental therapeutics.

[12]  K. Otani,et al.  Effects of Itraconazole on the Plasma Kinetics of Quazepam and Its Two Active Metabolites after a Single Oral Dose of the Drug , 2003, Therapeutic drug monitoring.

[13]  M. Lucena,et al.  Hepatotoxicity associated with the new antidepressants. , 2002, The Journal of clinical psychiatry.

[14]  Guengerich Fp,et al.  Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450. , 1986 .

[15]  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.

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

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

[18]  Pumford Nr,et al.  Protein targets of xenobiotic reactive intermediates. , 1997 .

[19]  L. Fieser.  Carcinogenic Activity, Structure, and Chemical Reactivity of Polynuclear Aromatic Hydrocarbons , 1938 .

[20]  P H Li,et al.  Actions of corticotropin-releasing factor or cortisol on follicle-stimulating hormone secretion by isolated pig pituitary cells. , 1993, Life sciences.

[21]  F. Lombardo,et al.  BIOACTIVATION OF THE NONTRICYCLIC ANTIDEPRESSANT NEFAZODONE TO A REACTIVE QUINONE-IMINE SPECIES IN HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROME P450 3A4 , 2005, Drug Metabolism and Disposition.

[22]  E. Miller,et al.  The Presence and Significance of Bound Aminoazo Dyes in the Livers of Rats Fed p-Dimethylaminoazobenzene , 1947 .

[23]  Stephen B Choi.  Nefazodone (Serzone) withdrawn because of hepatotoxicity. , 2003, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[24]  B. Arison,et al.  Microsomal metabolism of the 5-lipoxygenase inhibitor L-739,010: evidence for furan bioactivation. , 1996, Chemical research in toxicology.

[25]  P. Carrupt,et al.  Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[26]  J. Luyendyk,et al.  Inflammation and Drug Idiosyncrasy—Is There a Connection? , 2003, Journal of Pharmacology and Experimental Therapeutics.

[27]  B. Martin,et al.  Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[28]  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.

[29]  A. Marfat,et al.  Discovery of CP-199,330 and CP-199,331: two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity. , 1999, Bioorganic & medicinal chemistry letters.

[30]  L. Benet,et al.  Predictability of the covalent binding of acidic drugs in man. , 1993, Life sciences.

[31]  A. Burlingame,et al.  Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

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

[33]  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.

[34]  Michael P Holt,et al.  Drug-induced liver injury. , 2010, Handbook of experimental pharmacology.

[35]  P. Matzinger.  The Danger Model: A Renewed Sense of Self , 2002, Science.

[36]  F. Guengerich,et al.  Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450. , 1987, Journal of medicinal chemistry.

[37]  A. Kalgutkar,et al.  Pharmacokinetics and metabolism of a cysteinyl leukotriene-1 receptor antagonist from the heterocyclic chromanol series in rats: in vitro-in vivo correlation, gender-related differences, isoform identification, and comparison with metabolism in human hepatic tissue. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[38]  W. M. Lee,et al.  Drug-induced hepatotoxicity. , 1995, The New England journal of medicine.

[39]  P. Corey,et al.  Incidence of Adverse Drug Reactions in Hospitalized Patients , 2012 .

[40]  O. Chazouilleres,et al.  [Drug-induced hepatotoxicity. The 13th updated edition of the bibliographic database of drug-related liver injuries and responsible drugs]. , 2000, Gastroenterologie clinique et biologique.

[41]  Steven D. Cohen,et al.  Selective protein covalent binding and target organ toxicity. , 1997, Toxicology and applied pharmacology.

[42]  T. Baillie,et al.  Minimizing the potential for metabolic activation as an integral part of drug design. , 2005, Current opinion in drug discovery & development.

[43]  R. Haddock,et al.  Metabolic pathway of paroxetine in animals and man and the comparative pharmacological properties of its metabolites , 1989, Acta psychiatrica Scandinavica. Supplementum.

[44]  A. Kalgutkar,et al.  Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[45]  R. Gasser,et al.  Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase. , 1999, British journal of clinical pharmacology.

[46]  S. Wolfe,et al.  Timing of new black box warnings and withdrawals for prescription medications. , 2002, JAMA.

[47]  T. Baillie,et al.  Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation. , 2002, Chemical research in toxicology.

[48]  J. Boyd,et al.  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. , 2004, Journal of pharmaceutical and biomedical analysis.

[49]  M. Murray.  DRUG‐MEDIATED INACTIVATION OF CYTOCHROME P450 , 1997, Clinical and experimental pharmacology & physiology.

[50]  A. Kalgutkar,et al.  Identification of an N-methyl-4-phenylpyridinium-like metabolite of the antidiarrheal agent loperamide in human liver microsomes: underlying reason(s) for the lack of neurotoxicity despite the bioactivation event. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[51]  P. Jaillon.  Clinical Pharmacokinetics of Prazosin , 1980, Clinical pharmacokinetics.

[52]  D. W. Fry,et al.  CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. , 2003, Seminars in oncology.

[53]  E. Eger,et al.  Biotransformation of Halothane, Enflurane, Isoflurane, and Desflurane to Trifluoroacetylated Liver Proteins: Association Between Protein Acylation and Hepatic Injury , 1997, Anesthesia and analgesia.

[54]  M. Pirmohamed,et al.  Metabolism-dependent neutrophil cytotoxicity of amodiaquine: A comparison with pyronaridine and related antimalarial drugs. , 1998, Chemical research in toxicology.

[55]  P L Morselli,et al.  Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem. , 1992, Drug metabolism reviews.

[56]  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.

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

[58]  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.

[59]  G. Aislaitner,et al.  The metabolism of alicyclic amines to reactive iminium ion intermediates , 1994, European Journal of Drug Metabolism and Pharmacokinetics.

[60]  J. Pincemail,et al.  Peroxidase‐catalysed oxidation of different dibenzazepine derivatives , 1995, Archiv der Pharmazie.

[61]  N. Kaplowitz,et al.  Clinical Perspectives on Xenobiotic‐Induced Hepatotoxicity , 2004, Drug metabolism reviews.

[62]  J. Uetrecht,et al.  Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[63]  F. Guengerich,et al.  Cytochrome P-450-catalyzed hydroxylation and carboxylic acid ester cleavage of Hantzsch pyridine esters. , 1988, The Journal of biological chemistry.

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

[65]  P Smith,et al.  Concordance of the toxicity of pharmaceuticals in humans and in animals. , 2000, Regulatory toxicology and pharmacology : RTP.

[66]  P C Smith,et al.  Disposition and reactivity of ibuprofen and ibufenac acyl glucuronides in vivo in the rhesus monkey and in vitro with human serum albumin. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[67]  H. A. Cameron,et al.  The lupus syndrome induced by hydralazine: a common complication with low dose treatment. , 1984, British medical journal.

[68]  R Scott Obach,et al.  Biotransformation reactions of five-membered aromatic heterocyclic rings. , 2002, Chemical research in toxicology.

[69]  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.

[70]  Munir Pirmohamed,et al.  The role of metabolic activation in drug-induced hepatotoxicity. , 2005, Annual review of pharmacology and toxicology.

[71]  Jeffrey C Stevens,et al.  Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[72]  J. Gorrod,et al.  Trapping of reactive intermediates by incorporation of 14C-sodium cyanide during microsomal oxidation. , 1991, Advances in experimental medicine and biology.

[73]  J. Uetrecht.  METABOLISM OF DRUGS BY LEUKOCYTES , 1994, Drug metabolism and drug interactions.

[74]  M. Maftouh,et al.  Structure and stereochemistry of the active metabolite of clopidogrel. , 2002, Drug metabolism and disposition: the biological fate of chemicals.