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Cyanide Trapping of Iminium Ion Reactive Intermediates Followed by Detection and Structure Identification Using Liquid Chromatography−Tandem Mass Spectrometry (LC-MS/MS)

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The Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, and Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406
Cite this: Chem. Res. Toxicol. 2005, 18, 10, 1537–1544
Publication Date (Web):September 22, 2005
https://doi.org/10.1021/tx0501637
Copyright © 2005 American Chemical Society

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    Secondary and tertiary alicyclic amines are widely found in pharmaceuticals and environmental compounds. The formation of iminium ions as reactive intermediates in the metabolic activation of alicyclic amines has previously been investigated in radiometric assays where radiolabeled cyanide is typically employed. In this paper, we report a relatively high throughput LC-MS/MS method for the detection of the nonradiolabeled cyanide adduct formed in rat or human liver microsomal incubations via constant neutral loss scan followed by structural characterization using product ion scan on a triple quadrupole mass spectrometer. A total of 14 alicyclic amine compounds were investigated with the cyanide trapping LC-MS/MS screen and also with the glutathione (GSH) trapping screen, a well-established and commonly employed technique for reactive metabolite screening. Our results are found to be in general agreement with the previous metabolism reports for these compounds, demonstrating the effectiveness, speed, and simplicity of the cyanide trapping LC-MS/MS method to study the iminium ion intermediates from alicyclic amines and its complementarities to GSH trapping method for reactive metabolite screenings.

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     Northeastern University.

     GlaxoSmithKline Pharmaceuticals.

    *

     Corresponding author. Tel, 610-270-6291; fax, 610-270-4971; e-mail, [email protected].

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    7. Matthew K. Matlock, Tyler B. Hughes, Jayme L. Dahlin, S. Joshua Swamidass. Modeling Small-Molecule Reactivity Identifies Promiscuous Bioactive Compounds. Journal of Chemical Information and Modeling 2018, 58 (8) , 1483-1500. https://doi.org/10.1021/acs.jcim.8b00104
    8. Amit S. Kalgutkar . Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens. Chemical Research in Toxicology 2017, 30 (1) , 220-238. https://doi.org/10.1021/acs.chemrestox.6b00332
    9. Tyler B. Hughes, Na Le Dang, Grover P. Miller, and S. Joshua Swamidass . Modeling Reactivity to Biological Macromolecules with a Deep Multitask Network. ACS Central Science 2016, 2 (8) , 529-537. https://doi.org/10.1021/acscentsci.6b00162
    10. Richard A. Thompson, Emre M. Isin, Monday O. Ogese, Jerome T. Mettetal, and Dominic P. Williams . Reactive Metabolites: Current and Emerging Risk and Hazard Assessments. Chemical Research in Toxicology 2016, 29 (4) , 505-533. https://doi.org/10.1021/acs.chemrestox.5b00410
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    12. Abhishek Srivastava, Sreekanth Ramachandran, Shahul P. Hameed, VijayKamal Ahuja, and Vinayak P. Hosagrahara . Identification and Mitigation of a Reactive Metabolite Liability Associated with Aminoimidazoles. Chemical Research in Toxicology 2014, 27 (9) , 1586-1597. https://doi.org/10.1021/tx500212c
    13. Kevin J. Schneider and Anthony P. DeCaprio . Covalent Thiol Adducts Arising from Reactive Intermediates of Cocaine Biotransformation. Chemical Research in Toxicology 2013, 26 (11) , 1755-1764. https://doi.org/10.1021/tx4003116
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    15. Wenying Jian, Hua-Fen Liu, Weiping Zhao, Elliott Jones, Mingshe Zhu. Simultaneous Screening of Glutathione and Cyanide Adducts Using Precursor Ion and Neutral Loss Scans-Dependent Product Ion Spectral Acquisition and Data Mining Tools. Journal of the American Society for Mass Spectrometry 2012, 23 (5) , 964-976. https://doi.org/10.1007/s13361-012-0354-6
    16. Xiaochun Zhu, Nataraj Kalyanaraman, and Raju Subramanian . Enhanced Screening of Glutathione-Trapped Reactive Metabolites by In-Source Collision-Induced Dissociation and Extraction of Product Ion Using UHPLC-High Resolution Mass Spectrometry. Analytical Chemistry 2011, 83 (24) , 9516-9523. https://doi.org/10.1021/ac202280f
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    18. Feng Li, Jie Lu, and Xiaochao Ma . Profiling the Reactive Metabolites of Xenobiotics Using Metabolomic Technologies. Chemical Research in Toxicology 2011, 24 (5) , 744-751. https://doi.org/10.1021/tx200033v
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    20. Michael D. Mitchell, Mollisa M. Elrick, Jennie L. Walgren, Richard A. Mueller, Dale L. Morris and David C. Thompson. Peptide-Based In Vitro Assay for the Detection of Reactive Metabolites. Chemical Research in Toxicology 2008, 21 (4) , 859-868. https://doi.org/10.1021/tx700344m
    21. Paul F. Hollenberg, Ute M. Kent and Namandjé N. Bumpus. Mechanism-Based Inactivation of Human Cytochromes P450s: Experimental Characterization, Reactive Intermediates, and Clinical Implications. Chemical Research in Toxicology 2008, 21 (1) , 189-205. https://doi.org/10.1021/tx7002504
    22. Josh T. Pearson, Jan L. Wahlstrom, Leslie J. Dickmann, Santosh Kumar, James R. Halpert, Larry C. Wienkers, Robert S. Foti and Dan A. Rock. Differential Time-Dependent Inactivation of P450 3A4 and P450 3A5 by Raloxifene: A Key Role for C239 in Quenching Reactive Intermediates. Chemical Research in Toxicology 2007, 20 (12) , 1778-1786. https://doi.org/10.1021/tx700207u
    23. F. Peter Guengerich and, James S. MacDonald. Applying Mechanisms of Chemical Toxicity to Predict Drug Safety. Chemical Research in Toxicology 2007, 20 (3) , 344-369. https://doi.org/10.1021/tx600260a
    24. Saleh M. Khalil, Kevin R. MacKenzie, Mirjana Maletic-Savatic, Feng Li. Metabolic bioactivation of antidepressants: advance and underlying hepatotoxicity. Drug Metabolism Reviews 2024, 56 (2) , 97-126. https://doi.org/10.1080/03602532.2024.2313967
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    29. A. Yagmur Goren, Yasar K. Recepoglu, Yeojoon Yoon, Alireza Khataee. Insights into sustainability of engineered carbonaceous material-based technologies for advanced cyanide removal from wastewater. Alexandria Engineering Journal 2023, 73 , 69-88. https://doi.org/10.1016/j.aej.2023.04.031
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    31. David Nugroho, Saksit Chanthai, Won-Chun Oh, Rachadaporn Benchawattananon. Fluorophores - rich natural powder from selected medicinal plants for detection latent fingerprints and cyanide. Science Progress 2023, 106 (1) , 003685042311562. https://doi.org/10.1177/00368504231156217
    32. R. Scott Obach, Amit S. Kalgutkar. Reactive Electrophiles and Metabolic Activation. 2023https://doi.org/10.1016/B978-0-323-95488-4.00018-8
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    34. MARK P. GRILLO. Chemical Mechanisms in Toxicology. 2022, 703-743. https://doi.org/10.1002/9781119851042.ch21
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    36. Viraj G. Naik, Sharanabasava D. Hiremath, Ankit Thakuri, Vijay Hemmadi, Malabika Biswas, Mainak Banerjee, Amrita Chatterjee. A coumarin coupled tetraphenylethylene based multi-targeted AIEgen for cyanide ion and nitro explosive detection, and cellular imaging. The Analyst 2022, 147 (13) , 2997-3006. https://doi.org/10.1039/D2AN00040G
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    38. Douglas B. Craig, Mitchell S. Guimond. Analysis of cyanide using fluorogenic derivatization and capillary electrophoresis. Food Chemistry 2022, 370 , 131377. https://doi.org/10.1016/j.foodchem.2021.131377
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    48. Amit S. Kalgutkar, James P. Driscoll. Is there enough evidence to classify cycloalkyl amine substituents as structural alerts?. Biochemical Pharmacology 2020, 174 , 113796. https://doi.org/10.1016/j.bcp.2020.113796
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    50. Yuanfu Lu, Xue-Mei Zhao, Zhaoyong Hu, Li Wang, Feng Li. LC–MS-Based Metabolomics in the Study of Drug-Induced Liver Injury. Current Pharmacology Reports 2019, 5 (1) , 56-67. https://doi.org/10.1007/s40495-018-0144-3
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    52. Shuto Hosaka, Takuto Honda, Seon Hwa Lee, Tomoyuki Oe. Biomimetic trapping cocktail to screen reactive metabolites: use of an amino acid and DNA motif mixture as light/heavy isotope pairs differing in mass shift. Analytical and Bioanalytical Chemistry 2018, 410 (16) , 3847-3857. https://doi.org/10.1007/s00216-018-1057-z
    53. Ju-Hyun Kim, Won-Gu Choi, Ju-Yeon Moon, Joo Young Lee, Sangkyu Lee, Hye Suk Lee. Metabolomics-assisted metabolite profiling of itraconazole in human liver preparations. Journal of Chromatography B 2018, 1083 , 68-74. https://doi.org/10.1016/j.jchromb.2018.02.041
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    55. Zhican Wang, Ying Fang, Dan Rock, Ji Ma. Rapid screening and characterization of glutathione-trapped reactive metabolites using a polarity switch-based approach on a high-resolution quadrupole orbitrap mass spectrometer. Analytical and Bioanalytical Chemistry 2018, 410 (5) , 1595-1606. https://doi.org/10.1007/s00216-017-0814-8
    56. Axel Pähler. Reactive Metabolite Assessment in Drug Discovery and Development in Support of Safe Drug Design. 2018, 263-281. https://doi.org/10.1007/978-1-4939-7677-5_13
    57. R.S. Obach, A.S. Kalgutkar. Reactive Electrophiles and Metabolic Activation. 2018, 295-331. https://doi.org/10.1016/B978-0-12-801238-3.64290-3
    58. Jun Hosogi, Rui Ohashi, Hiroshi Maeda, Satoshi Tashiro, Eiichi Fuse, Yorihiro Yamamoto, Takashi Kuwabara. Monoamine oxidase B oxidizes a novel multikinase inhibitor KW-2449 to its iminium ion and aldehyde oxidase further converts it to the oxo-piperazine form in human. Drug Metabolism and Pharmacokinetics 2017, 32 (5) , 255-264. https://doi.org/10.1016/j.dmpk.2017.06.002
    59. Andreas Brink, Axel Pähler, Christoph Funk, Franz Schuler, Simone Schadt. Minimizing the risk of chemically reactive metabolite formation of new drug candidates: implications for preclinical drug design. Drug Discovery Today 2017, 22 (5) , 751-756. https://doi.org/10.1016/j.drudis.2016.11.018
    60. Amanda L. Cirello, Jennifer L. Dumouchel, Mithat Gunduz, Christine E. Dunne, Upendra A. Argikar. In vitro ocular metabolism and bioactivation of ketoconazole in rat, rabbit and human. Drug Metabolism and Pharmacokinetics 2017, 32 (2) , 121-126. https://doi.org/10.1016/j.dmpk.2016.11.001
    61. Zhican Wang, Brooke M Rock, Josh T Pearson, Thuy Tran, Dan A Rock. Characterization of Nefazodone Time‐dependent Inhibition of Cytochrome P450 3A. The FASEB Journal 2017, 31 (S1) https://doi.org/10.1096/fasebj.31.1_supplement.669.9
    62. Ju-Hyun Kim, Won-Gu Choi, Sangkyu Lee, Hye Lee. Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics. International Journal of Molecular Sciences 2017, 18 (3) , 621. https://doi.org/10.3390/ijms18030621
    63. Sawsan M. Amer, Adnan A. Kadi, Hany W. Darwish, Mohamed W. Attwa. Identification and characterization of in vitro phase I and reactive metabolites of masitinib using a LC-MS/MS method: bioactivation pathway elucidation. RSC Advances 2017, 7 (8) , 4479-4491. https://doi.org/10.1039/C6RA25767D
    64. J. Gerry Kenna, Richard A. Thompson. INTEGRATED REACTIVE METABOLITE STRATEGIES. 2016, 111-139. https://doi.org/10.1002/9781118949689.ch5
    65. M. José Gómez‐Lechón, Laia Tolosa, M. Teresa Donato. Metabolic activation and drug‐induced liver injury: in vitro approaches for the safety risk assessment of new drugs. Journal of Applied Toxicology 2016, 36 (6) , 752-768. https://doi.org/10.1002/jat.3277
    66. Avishek Karmakar, Naveen Kumar, Partha Samanta, Aamod V. Desai, Sujit K. Ghosh. A Post‐Synthetically Modified MOF for Selective and Sensitive Aqueous‐Phase Detection of Highly Toxic Cyanide Ions. Chemistry – A European Journal 2016, 22 (3) , 864-868. https://doi.org/10.1002/chem.201503323
    67. Adnan A. Kadi, Hany W. Darwish, Mohamed W. Attwa, Sawsan M. Amer. Detection and characterization of ponatinib reactive metabolites by liquid chromatography tandem mass spectrometry and elucidation of bioactivation pathways. RSC Advances 2016, 6 (76) , 72575-72585. https://doi.org/10.1039/C6RA09985H
    68. Thomas A. Baillie. Chemically Reactive Versus Stable Drug Metabolites: Role in Adverse Drug Reactions. 2015, 202-226. https://doi.org/10.1039/9781782622376-00202
    69. Toshikazu Yamaoka, Yoshiaki Kitamura. Characterization of a highly sensitive and selective novel trapping reagent, stable isotope labeled glutathione ethyl ester, for the detection of reactive metabolites. Journal of Pharmacological and Toxicological Methods 2015, 76 , 83-95. https://doi.org/10.1016/j.vascn.2015.08.157
    70. Xing Liu, Yuanfu Lu, Xinfu Guan, Bingning Dong, Hemantkumar Chavan, Jin Wang, Yiqing Zhang, Partha Krishnamurthy, Feng Li. Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism. Biochemical Pharmacology 2015, 97 (1) , 111-121. https://doi.org/10.1016/j.bcp.2015.07.010
    71. Dennis S.B. Ongarora, Natasha Strydom, Kathryn Wicht, Mathew Njoroge, Lubbe Wiesner, Timothy J. Egan, Sergio Wittlin, Ulrik Jurva, Collen M. Masimirembwa, Kelly Chibale. Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies. Bioorganic & Medicinal Chemistry 2015, 23 (17) , 5419-5432. https://doi.org/10.1016/j.bmc.2015.07.051
    72. Mark P Grillo. Detecting reactive drug metabolites for reducing the potential for drug toxicity. Expert Opinion on Drug Metabolism & Toxicology 2015, 11 (8) , 1281-1302. https://doi.org/10.1517/17425255.2015.1048222
    73. Toshihiko Ikeda. Recent Findings Regarding the Mechanism of Idiosyncratic Drug Toxicity. YAKUGAKU ZASSHI 2015, 135 (4) , 567-578. https://doi.org/10.1248/yakushi.14-00249-1
    74. Jaana E. Laine, Merja R. Häkkinen, Seppo Auriola, Risto O. Juvonen, Markku Pasanen. Comparison of trapping profiles between d -peptides and glutathione in the identification of reactive metabolites. Toxicology Reports 2015, 2 , 1024-1032. https://doi.org/10.1016/j.toxrep.2015.07.002
    75. Fumio Osaki, Takaaki Goto, Seon Hwa Lee, Tomoyuki Oe. Predicted multiple selected reaction monitoring to screen activated drug-mediated modifications on human serum albumin. Analytical Biochemistry 2014, 449 , 59-67. https://doi.org/10.1016/j.ab.2013.12.016
    76. Tonika Bohnert, Lawrence L. Gan. In Vitro Experimental Models for Studying Drug Biotransformation. 2013, 1-61. https://doi.org/10.1002/9781118541203.xen0015
    77. Andrew V. Stachulski, Thomas A. Baillie, B. Kevin Park, R. Scott Obach, Deepak K. Dalvie, Dominic P. Williams, Abhishek Srivastava, Sophie L. Regan, Daniel J. Antoine, Christopher E. P. Goldring, Alvin J. L. Chia, Neil R. Kitteringham, Laura E. Randle, Hayley Callan, J. Luis Castrejon, John Farrell, Dean J. Naisbitt, Martin S. Lennard. The Generation, Detection, and Effects of Reactive Drug Metabolites. Medicinal Research Reviews 2013, 33 (5) , 985-1080. https://doi.org/10.1002/med.21273
    78. Alison V. M. Rodrigues, Helen E. Rollison, Scott Martin, Sunil Sarda, Timothy Schulz-Utermoehl, Simone Stahl, Frida Gustafsson, Julie Eakins, J. Gerry Kenna, Ian D. Wilson. In vitro exploration of potential mechanisms of toxicity of the human hepatotoxic drug fenclozic acid. Archives of Toxicology 2013, 87 (8) , 1569-1579. https://doi.org/10.1007/s00204-013-1056-y
    79. Jens Atzrodt, Volker Derdau. Selected Scientific Topics of the 11th International Isotope Symposium on the Synthesis and Applications of Isotopes and Isotopically Labeled Compounds. Journal of Labelled Compounds and Radiopharmaceuticals 2013, 56 (9-10) , 408-416. https://doi.org/10.1002/jlcr.3096
    80. Amit S. Kalgutkar, Tim F. Ryder, Gregory S. Walker, Suvi T. M. Orr, Shawn Cabral, Theunis C. Goosen, Kimberly Lapham, Heather Eng. Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1- b ]thiazole-Based Inverse Agonists of the Ghrelin Receptor. Drug Metabolism and Disposition 2013, 41 (7) , 1375-1388. https://doi.org/10.1124/dmd.113.051839
    81. Minli Zhang, Christina M. Resuello, Jian Guo, Mark E. Powell, Charles S. Elmore, Jun Hu, Karthick Vishwanathan. Contribution of Artifacts to N -Methylated Piperazine Cyanide Adduct Formation In Vitro from N -Alkyl Piperazine Analogs. Drug Metabolism and Disposition 2013, 41 (5) , 1023-1034. https://doi.org/10.1124/dmd.112.050450
    82. Sanja Dragovic, Patrina Gunness, Magnus Ingelman-Sundberg, Nico P.E. Vermeulen, Jan N. M. Commandeur. Characterization of Human Cytochrome P450s Involved in the Bioactivation of Clozapine. Drug Metabolism and Disposition 2013, 41 (3) , 651-658. https://doi.org/10.1124/dmd.112.050484
    83. Douglas K. Spracklin, Amit S. Kalgutkar, Angus N. R. Nedderman. The Role of Biotransformation Studies in Reducing Drug Attrition. 2013, 97-137. https://doi.org/10.1007/7355_2012_18
    84. . Experimental Approaches to Reactive Metabolite Detection. 2012, 225-240. https://doi.org/10.1002/9783527655748.ch10
    85. Joanna E. Barbara, Faraz Kazmi, Seema Muranjan, Paul C. Toren, Andrew Parkinson. High-Resolution Mass Spectrometry Elucidates Metabonate (False Metabolite) Formation from Alkylamine Drugs during In Vitro Metabolite Profiling. Drug Metabolism and Disposition 2012, 40 (10) , 1966-1975. https://doi.org/10.1124/dmd.112.047027
    86. Scott Martin, Eva M. Lenz, Dave Temesi, Martin Wild, Malcolm R. Clench. Reaction of Homopiperazine with Endogenous Formaldehyde: A Carbon Hydrogen Addition Metabolite/Product Identified in Rat Urine and Blood. Drug Metabolism and Disposition 2012, 40 (8) , 1478-1486. https://doi.org/10.1124/dmd.112.044917
    87. Jane R. Kenny, Sophie Mukadam, Chenghong Zhang, Suzanne Tay, Carol Collins, Aleksandra Galetin, S. Cyrus Khojasteh. Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction. Pharmaceutical Research 2012, 29 (7) , 1960-1976. https://doi.org/10.1007/s11095-012-0724-6
    88. Sandra Jahn, Helene Faber, Raniero Zazzeroni, Uwe Karst. Electrochemistry/mass spectrometry as a tool in the investigation of the potent skin sensitizer p ‐phenylenediamine and its reactivity toward nucleophiles. Rapid Communications in Mass Spectrometry 2012, 26 (12) , 1453-1464. https://doi.org/10.1002/rcm.6249
    89. Hayley M. Webb, Sophie Regan, Daniel J. Antoine, Nicola Lane, Rachel J. Walsh, Abhishek Srivastava, Philip Starkey‐Lewis, Craig Benson, Dominic P. Williams, Hugh Laverty, Christopher Goldring, B. Kevin Park. Drug Bioactivation and Oxidative Stress. 2012, 1-44. https://doi.org/10.1002/9780470921920.edm053
    90. Amit S. Kalgutkar, Jonathan N. Bauman. Role of Metabolism in Toxicity of Drugs in Humans. 2012, 1-26. https://doi.org/10.1002/9780470921920.edm127
    91. Cen Xie, Dafang Zhong, Kate Yu, Xiaoyan Chen. Recent Advances in Metabolite Identification And Quantitative Bioanalysis By Lc–Q-Tof Ms. Bioanalysis 2012, 4 (8) , 937-959. https://doi.org/10.4155/bio.12.43
    92. W. Griffith Humphreys. Pharmacological and Toxicological Activity of Drug Metabolites. 2012, 55-65. https://doi.org/10.1002/9781118180778.ch4
    93. Feng Li, Frank J. Gonzalez, Xiaochao Ma. LC–MS-based metabolomics in profiling of drug metabolism and bioactivation. Acta Pharmaceutica Sinica B 2012, 2 (2) , 118-125. https://doi.org/10.1016/j.apsb.2012.02.010
    94. Louis Leung, Amit S. Kalgutkar, R. Scott Obach. Metabolic activation in drug-induced liver injury. Drug Metabolism Reviews 2012, 44 (1) , 18-33. https://doi.org/10.3109/03602532.2011.605791
    95. Scott R. Obach, Deepak K. Dalvie, Gregory S. Walker. Identification of Drug Metabolites. 2012, 1-55. https://doi.org/10.1002/9780470921920.edm052
    96. Thomas A. Baillie. Drug Metabolism in Drug Safety Evaluation. 2012, 1-24. https://doi.org/10.1002/9780470921920.edm054
    97. James M. MKim. In Vitro Toxicity Screening in Early Drug Discovery: Importance of Metabolism and Reactive Metabolites. 2012, 1-28. https://doi.org/10.1002/9780470921920.edm077
    98. Joanna E. Barbara, Jose M. Castro‐Perez. High‐resolution chromatography/time‐of‐flight MS E with in silico data mining is an information‐rich approach to reactive metabolite screening. Rapid Communications in Mass Spectrometry 2011, 25 (20) , 3029-3040. https://doi.org/10.1002/rcm.5197
    99. Sophie C. Turfus, Robin A Braithwaite, David A. Cowan, Mark C. Parkin, Norman W. Smith, Andrew T. Kicman. Metabolites of lorazepam: Relevance of past findings to present day use of LC‐MS/MS in analytical toxicology. Drug Testing and Analysis 2011, 3 (10) , 695-704. https://doi.org/10.1002/dta.305
    100. Moa Andresen Bergström, Emre M. Isin, Neal Castagnoli, Claire E. Milne. Bioactivation Pathways of the Cannabinoid Receptor 1 Antagonist Rimonabant. Drug Metabolism and Disposition 2011, 39 (10) , 1823-1832. https://doi.org/10.1124/dmd.111.039412
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