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Metabolites in Safety Testing (MIST): Considerations of Mechanisms of Toxicity with Dose, Abundance, and Duration of Treatment

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Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Sandwich, Kent, U.K., and Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Groton, Connecticut
* To whom correspondence should be addressed. E-mail: [email protected]
†Pfizer Inc., Sandwich, Kent.
‡Pfizer Inc., Groton, Connecticut.
Cite this: Chem. Res. Toxicol. 2009, 22, 2, 267–279
Publication Date (Web):January 23, 2009
https://doi.org/10.1021/tx800415j
Copyright © 2009 American Chemical Society
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    Abstract

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    In previous papers, we have offered a strategic framework regarding metabolites of drugs in humans and the need to assess these in laboratory animal species (also termed Metabolites in Safety Testing or MIST; Smith and Obach, Chem. Res. Toxicol. (2006) 19, 1570−1579). Three main tenets of this framework were founded in (i) comparisons of absolute exposures (as circulating concentrations or total body burden), (ii) the nature of the toxicity mechanism (i.e., reversible interaction at specific targets versus covalent binding to multiple macromolecules), and (iii) the biological matrix in which the metabolite was observed (circulatory vs excretory). In the present review, this framework is expanded to include a fourth tenet: considerations for the duration of exposure. Basic concepts of pharmacology are utilized to rationalize the relationship between exposure (to parent drug or metabolite) and various effects ranging from desired therapeutic effects through to severe toxicities. Practical considerations of human ADME (absorption−distribution−metabolism−excretion) data, to determine which metabolites should be further evaluated for safety, are discussed. An analysis of recently published human ADME studies shows that the number of drug metabolites considered to be important for MIST can be excessively high if a simple percentage-of-parent-drug criterion is used without consideration of the aforementioned four tenets. Concern over unique human metabolites has diminished over the years as experience has shown that metabolites of drugs in humans will almost always be observed in laboratory animals, although the proportions may vary. Even if a metabolite represents a high proportion of the dose in humans and a low proportion in animals, absolute abundances in animals frequently exceed that in humans because the doses used in animal toxicology studies are much greater than therapeutic doses in humans. The review also updates the enzymatic basis for the differences between species and how these relate to MIST considerations.

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    8. Aisar H. Atrakchi. Interpretation and Considerations on the Safety Evaluation of Human Drug Metabolites. Chemical Research in Toxicology 2009, 22 (7) , 1217-1220. https://doi.org/10.1021/tx900124j
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    15. Raine E.S. Thomson, Stephlina A. D’Cunha, Martin A. Hayes, Elizabeth M.J. Gillam. Use of engineered cytochromes P450 for accelerating drug discovery and development. 2022, 195-252. https://doi.org/10.1016/bs.apha.2022.06.001
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    27. Julien Genovino, Dalibor Sames, Lawrence G. Hamann, B. Barry Touré. Accessing Drug Metabolites via Transition‐Metal Catalyzed C−H Oxidation: The Liver as Synthetic Inspiration. Angewandte Chemie International Edition 2016, 55 (46) , 14218-14238. https://doi.org/10.1002/anie.201602644
    28. B. Kevin Park, Dennis A. Smith. MIST AND THE FUTURE. 2016, 305-322. https://doi.org/10.1002/9781118949689.ch14
    29. Gordon J. Dear, Angus N. R. Nedderman. “MIST” AND OTHER METABOLITE GUIDELINES IN THE CONTEXT OF INDUSTRIAL DRUG METABOLISM. 2016, 17-43. https://doi.org/10.1002/9781118949689.ch2
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    48. Gregory S. Walker, Jonathan N. Bauman, Tim F. Ryder, Evan B. Smith, Douglas K. Spracklin, R. Scott Obach. Biosynthesis of Drug Metabolites and Quantitation Using NMR Spectroscopy for Use in Pharmacologic and Drug Metabolism Studies. Drug Metabolism and Disposition 2014, 42 (10) , 1627-1639. https://doi.org/10.1124/dmd.114.059204
    49. Dan Xu, Toshi Nishimura, Sachiko Nishimura, Haili Zhang, Ming Zheng, Ying-Ying Guo, Marylin Masek, Sara A. Michie, Jeffrey Glenn, Gary Peltz, . Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing. PLoS Medicine 2014, 11 (4) , e1001628. https://doi.org/10.1371/journal.pmed.1001628
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    52. W. Griffith Humphreys. In Vivo Experimental Models for Studying Drug Biotransformation. 2014, 1-10. https://doi.org/10.1002/9781118541203.xen0016
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    56. Tonika Bohnert, Liang-Shang Gan. Plasma protein binding: From discovery to development. Journal of Pharmaceutical Sciences 2013, 102 (9) , 2953-2994. https://doi.org/10.1002/jps.23614
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    58. 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
    59. Marzena Poraj‐Kobielska, Jens Atzrodt, Wolfgang Holla, Martin Sandvoss, Glenn Gröbe, Katrin Scheibner, Martin Hofrichter. Preparation of labeled human drug metabolites and drug‐drug interaction‐probes with fungal peroxygenases. Journal of Labelled Compounds and Radiopharmaceuticals 2013, 56 (9-10) , 513-519. https://doi.org/10.1002/jlcr.3103
    60. Xiaochun Zhu, J. Greg Slatter, Maurice G. Emery, Molly R. Deane, Anna Akrami, Xiping Zhang, Dean Hickman, Gary L. Skiles, Raju Subramanian. Activity-based exposure comparisons among humans and nonclinical safety testing species in an extensively metabolized drug candidate. Xenobiotica 2013, 43 (7) , 617-627. https://doi.org/10.3109/00498254.2012.747711
    61. Gary Peltz. Can ‘humanized’ mice improve drug development in the 21st century?. Trends in Pharmacological Sciences 2013, 34 (5) , 255-260. https://doi.org/10.1016/j.tips.2013.03.005
    62. 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
    63. Anja Ekdahl, Ann Aurell-Holmberg, Neal Castagnoli. Identification of the metabolites of lesogaberan using linear trap quadrupole orbitrap mass spectrometry and hydrophilic interaction liquid chromatography. Xenobiotica 2013, 43 (5) , 461-467. https://doi.org/10.3109/00498254.2012.725486
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    65. Kedan Lin, Jay Tibbitts, Ben-Quan Shen. Pharmacokinetics and ADME Characterizations of Antibody–Drug Conjugates. 2013, 117-131. https://doi.org/10.1007/978-1-62703-541-5_7
    66. Jim Vrbanac, Richard Slauter. ADME in Drug Discovery. 2013, 3-30. https://doi.org/10.1016/B978-0-12-387815-1.00002-2
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    68. Sebastian Schulz, Marco Girhard, Vlada B. Urlacher. Biocatalysis: Key to Selective Oxidations. ChemCatChem 2012, 4 (12) , 1889-1895. https://doi.org/10.1002/cctc.201200533
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    75. Kiumars Shahrokh, Thomas E. Cheatham, Garold S. Yost. Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen. Biochimica et Biophysica Acta (BBA) - General Subjects 2012, 1820 (10) , 1605-1617. https://doi.org/10.1016/j.bbagen.2012.05.011
    76. Kedan Lin, Jay Tibbitts. Pharmacokinetic Considerations for Antibody Drug Conjugates. Pharmaceutical Research 2012, 29 (9) , 2354-2366. https://doi.org/10.1007/s11095-012-0800-y
    77. Ryan D. Morrison, Anna L. Blobaum, Frank W. Byers, Tammy S. Santomango, Thomas M. Bridges, Donald Stec, Katrina A. Brewer, Raymundo Sanchez-Ponce, Melany M. Corlew, Roger Rush, Andrew S. Felts, Jason Manka, Brittney S. Bates, Daryl F. Venable, Alice L. Rodriguez, Carrie K. Jones, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte, J. Scott Daniels. The Role of Aldehyde Oxidase and Xanthine Oxidase in the Biotransformation of a Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5. Drug Metabolism and Disposition 2012, 40 (9) , 1834-1845. https://doi.org/10.1124/dmd.112.046136
    78. Debra Luffer-Atlas. The early estimation of circulating drug metabolites in humans. Expert Opinion on Drug Metabolism & Toxicology 2012, 8 (8) , 985-997. https://doi.org/10.1517/17425255.2012.693159
    79. Hongying Gao, R. Scott Obach. A Simple Liquid Chromatography-Tandem Mass Spectrometry Method to Determine Relative Plasma Exposures of Drug Metabolites across Species for Metabolite Safety Assessments (Metabolites in Safety Testing). II. Application to Unstable Metabolites. Drug Metabolism and Disposition 2012, 40 (7) , 1290-1296. https://doi.org/10.1124/dmd.112.044552
    80. Chandra Prakash, Zhaoyang Li, Cesare Orlandi, Lewis Klunk. Assessment of Exposure of Metabolites in Preclinical Species and Humans at Steady State from the Single-Dose Radiolabeled Absorption, Distribution, Metabolism, and Excretion Studies: A Case Study. Drug Metabolism and Disposition 2012, 40 (7) , 1308-1320. https://doi.org/10.1124/dmd.112.044933
    81. Elizabeth Rayburn, Wei Wang, Mao Li, Xu Zhang, Hongxia Xu, Haibo Li, Jiang-Jiang Qin, Lee Jia, Joseph Covey, Moses Lee, Ruiwen Zhang. Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent. Cancer Chemotherapy and Pharmacology 2012, 69 (6) , 1423-1431. https://doi.org/10.1007/s00280-012-1851-9
    82. Michael D. Coleman, Louis L. Radulovic. Clinical Aspects of Drug Biotransformation: An OverviewDedicated to the memory of Mark J. Winn, Ph.D.,1960–1993. 2012, 1-50. https://doi.org/10.1002/9780470921920.edm116
    83. W. Griffith Humphreys. Pharmacological and Toxicological Activity of Drug Metabolites. 2012, 55-65. https://doi.org/10.1002/9781118180778.ch4
    84. Asoka Ranasinghe, Ragu Ramanathan, Mohammed Jemal, Celia J D’Arienzo, W Griffith Humphreys, Timothy V Olah. Integrated quantitative and qualitative workflow for in vivo bioanalytical support in drug discovery using hybrid Q-TOF-MS. Bioanalysis 2012, 4 (5) , 511-528. https://doi.org/10.4155/bio.12.13
    85. Xinsheng Gu, Jose E. Manautou. Molecular mechanisms underlying chemical liver injury. Expert Reviews in Molecular Medicine 2012, 14 https://doi.org/10.1017/S1462399411002110
    86. Thomas A. Baillie. Drug Metabolism in Drug Safety Evaluation. 2012, 1-24. https://doi.org/10.1002/9780470921920.edm054
    87. Walter A. Korfmacher. Bioanalytical Support for Both In Vitro and In Vivo Assays Across Drug Discovery and Drug Development. 2012, 1-18. https://doi.org/10.1002/9780470921920.edm090
    88. Hannah M Jones, Maurice Dickins, Kuresh Youdim, James R Gosset, Neil J Attkins, Tanya L Hay, Ian K Gurrell, Y Raj Logan, Peter J Bungay, Barry C Jones, Iain B Gardner. Application of PBPK modelling in drug discovery and development at Pfizer. Xenobiotica 2012, 42 (1) , 94-106. https://doi.org/10.3109/00498254.2011.627477
    89. Dennis A. Smith, Deepak Dalvie. Why do metabolites circulate?. Xenobiotica 2012, 42 (1) , 107-126. https://doi.org/10.3109/00498254.2011.630110
    90. Vanina Rea, Sanja Dragovic, Jan Simon Boerma, Frans J. J. de Kanter, Nico P. E. Vermeulen, Jan N. M. Commandeur. Role of Residue 87 in the Activity and Regioselectivity of Clozapine Metabolism by Drug-Metabolizing CYP102A1 M11H: Application for Structural Characterization of Clozapine GSH Conjugates. Drug Metabolism and Disposition 2011, 39 (12) , 2411-2420. https://doi.org/10.1124/dmd.111.041046
    91. Jelle Reinen, Jolanda S. van Leeuwen, Yongmin Li, Lifang Sun, Peter D. J. Grootenhuis, Caroline J. Decker, John Saunders, Nico P. E. Vermeulen, Jan N. M. Commandeur. Efficient Screening of Cytochrome P450 BM3 Mutants for Their Metabolic Activity and Diversity toward a Wide Set of Drug-Like Molecules in Chemical Space. Drug Metabolism and Disposition 2011, 39 (9) , 1568-1576. https://doi.org/10.1124/dmd.111.039461
    92. Christiane K. Fæste, Lada Ivanova, Silvio Uhlig. In Vitro Metabolism of the Mycotoxin Enniatin B in Different Species and Cytochrome P450 Enzyme Phenotyping by Chemical Inhibitors. Drug Metabolism and Disposition 2011, 39 (9) , 1768-1776. https://doi.org/10.1124/dmd.111.039529
    93. Nigel Greene, Minghu Song. Predicting in vivo safety characteristics using physiochemical properties and in vitro assays. Future Medicinal Chemistry 2011, 3 (12) , 1503-1511. https://doi.org/10.4155/fmc.11.89
    94. Angus N.R. Nedderman, Gordon J. Dear, Stephanie North, R. Scott Obach, David Higton. From definition to implementation: a cross-industry perspective of past, current and future MIST strategies. Xenobiotica 2011, 41 (8) , 605-622. https://doi.org/10.3109/00498254.2011.562330
    95. Ronald E. White. Progression of Drug Metabolism. 2011, 1-12. https://doi.org/10.1002/9780470929278.ch1
    96. W. Griffith Humphreys. Drug Metabolism Research as Integral Part of Drug Discovery and Development Processes. 2011, 229-253. https://doi.org/10.1002/9780470929278.ch7
    97. Leposava Antonovic, Marilyn Martinez. Role of the cytochrome P450 enzyme system in veterinary pharmacokinetics: where are we now? Where are we going?. Future Medicinal Chemistry 2011, 3 (7) , 855-879. https://doi.org/10.4155/fmc.11.37
    98. Akiko Baba, Tadao Yoshioka. Characterization of chemo- and regioselectivity in enzyme-catalyzed consecutive hydrolytic deprotection of methyl acetyl derivatives of 1-β-O-acyl glucuronides. Journal of Molecular Catalysis B: Enzymatic 2011, 69 (1-2) , 74-82. https://doi.org/10.1016/j.molcatb.2010.12.014
    99. B. Kevin Park, Alan Boobis, Stephen Clarke, Chris E. P. Goldring, David Jones, J. Gerry Kenna, Craig Lambert, Hugh G. Laverty, Dean J. Naisbitt, Sidney Nelson, Deborah A. Nicoll-Griffith, R. Scott Obach, Philip Routledge, Dennis A. Smith, Donald J. Tweedie, Nico Vermeulen, Dominic P. Williams, Ian D. Wilson, Thomas A. Baillie. Managing the challenge of chemically reactive metabolites in drug development. Nature Reviews Drug Discovery 2011, 10 (4) , 292-306. https://doi.org/10.1038/nrd3408
    100. Wenying Jian, Yaodong Xu, Richard W Edom, Naidong Weng. Analysis of polar metabolites by hydrophilic interaction chromatography–MS/MS. Bioanalysis 2011, 3 (8) , 899-912. https://doi.org/10.4155/bio.11.51
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