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Which Human Metabolites Have We MIST? Retrospective Analysis, Practical Aspects, and Perspectives For Metabolite Identification and Quantification in Pharmaceutical Development

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Department of Drug Metabolism and Pharmacokinetics, Global Preclinical Development, Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey
* Corresponding author. Tel: +32/(0)14 607094. Fax: +32/(0)14 605110. E-mail: [email protected]
†Johnson & Johnson Pharmaceutical Research and Development.
‡Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Cite this: Chem. Res. Toxicol. 2009, 22, 2, 280–293
Publication Date (Web):January 30, 2009
Copyright © 2009 American Chemical Society

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    With the recent publication of the FDA guidance on metabolites in safety testing (MIST), a reflection is provided that describes the impact of this guidance on the processes of drug metabolite identification and quantification at various stages of drug development. First, a retrospective analysis is described that was conducted on 12 human absorption, metabolism, and excretion (AME) trials with the application of these MIST criteria. This analysis showed that the number of metabolites requiring identification, (semi)-quantification, and coverage in the toxicology species would substantially increase. However, a significant proportion of these metabolites were direct or indirect conjugates, a class of metabolites that was specifically addressed in the guidance as being largely innocuous. The nonconjugated metabolites were all covered in at least one toxicology animal species, with no need for additional safety evaluation. Second, analytical considerations pertaining to the efficient identification of metabolites are discussed. Topics include software-assisted detection and structural identification of metabolites, the emerging hyphenation of ultraperformance liquid chromatography (UPLC) with radioactivity detection, and the various ways to estimate metabolite abundance in the absence of an authentic standard. Technical aspects around the analysis of metabolite profiles are also presented, focusing on precautions to be taken in order not to introduce artifacts. Finally, a tiered approach for metabolite quantification is proposed, starting with quantification of metabolites prior to the multiple ascending dose study (MAD) in humans in only specific cases (Tier A). The following step is the identification and quantification of metabolites expected to be of pharmacological or toxicological relevance (based on MIST and other complementary criteria) in selected samples from the MAD study and preclinical studies in order to assess metabolite exposure coverage (Tier B). Finally, a metabolite quantification strategy for the studies after the MAD phase (Tier C) is proposed.

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    3. 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.
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    5. Stephen B. Milne, Thomas P. Mathews, David S. Myers, Pavlina T. Ivanova, and H. Alex Brown . Sum of the Parts: Mass Spectrometry-Based Metabolomics. Biochemistry 2013, 52 (22) , 3829-3840.
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    8. Wenying Jian, Ming Yao, Duxi Zhang and Mingshe Zhu . Rapid Detection and Characterization of in Vitro and Urinary N-Acetyl-l-cysteine Conjugates Using Quadrupole-Linear Ion Trap Mass Spectrometry and Polarity Switching. Chemical Research in Toxicology 2009, 22 (7) , 1246-1255.
    9. Wenkui Li, Faye Vazvaei‐Smith, Gordon Dear, Jason Boer, Filip Cuyckens, Daniela Fraier, Yuexia Liang, Ding Lu, Heidi Mangus, Patricia Moliner, Mette Lund Pedersen, Andrea A. Romeo, Douglas K. Spracklin, David S. Wagner, Serge Winter, Xiaohui (Sophia) Xu. Metabolite Bioanalysis in Drug Development: Recommendations from the IQ Consortium Metabolite Bioanalysis Working Group. Clinical Pharmacology & Therapeutics 2024, 115 (5) , 939-953.
    10. Filip Cuyckens, Mette G. Hvenegaard, Kenneth C. Cassidy, Douglas K. Spracklin, Alexander D. James, Mette L. Pedersen, Graeme Scarfe, David S. Wagner, Katrin Georgi, Simone I. Schulz, Hanno Schieferstein, Inga Bjornsdottir, Andrea A. Romeo, Georges Da Violante, Stefan Blech, Patricia Moliner, Graeme C. Young. Recommendations on the Use of Multiple Labels in Human Mass Balance Studies. Drug Metabolism and Disposition 2024, 52 (3) , 153-158.
    11. Wenkui Li, Franck Picard. Toxicokinetics in preclinical drug development of small‐molecule new chemical entities. Biomedical Chromatography 2023, 37 (7)
    12. Ibrahim M. Alanazi, Abdullah R. Alzahrani, Torki A. Zughaibi, Ahmed I. Al-Asmari, Shams Tabrez, Catherine Henderson, David Watson, Mary Helen Grant. Metabolomics Analysis as a Tool to Measure Cobalt Neurotoxicity: An In Vitro Validation. Metabolites 2023, 13 (6) , 698.
    13. R. Lock, P. J. H. Webborn, C. W. Vose, R. M. J. Ings. Drug Metabolism. 2023, 265-297.
    14. Simon G. Wong, Shuguang Ma. Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development. 2023, 137-174.
    15. Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H. Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K. Malhotra, Martin E. Dowty. The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans. Drug Metabolism and Disposition 2022, 50 (8) , 1106-1118.
    16. Xiaoxing Wang, Martin E. Dowty, Ann Wouters, Svitlana Tatulych, Carol A. Connell, Vu H. Le, Sakambari Tripathy, Melissa T. O’Gorman, Jennifer A. Winton, Natalie Yin, Hernan Valdez, Bimal K. Malhotra. Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals. European Journal of Drug Metabolism and Pharmacokinetics 2022, 47 (3) , 419-429.
    17. Ellen Q. Wang, Vu Le, Melissa O'Gorman, Sakambari Tripathy, Martin E. Dowty, Lisy Wang, Bimal K. Malhotra. Effects of Hepatic Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites. The Journal of Clinical Pharmacology 2021, 61 (10) , 1311-1323.
    18. Enaksha R Wickremsinhe, Lisa B Lee. Quantification of Abemaciclib and Metabolites: Evolution of Bioanalytical Methods Supporting a Novel Oncolytic Agent. Bioanalysis 2021, 13 (9) , 711-724.
    19. Bianca D. van Groen, Esther van Duijn, Arjan de Vries, Miriam G. Mooij, Dick Tibboel, Wouter H. J. Vaes, Saskia N. de Wildt. Proof of Concept: First Pediatric [ 14 C]microtracer Study to Create Metabolite Profiles of Midazolam. Clinical Pharmacology & Therapeutics 2020, 108 (5) , 1003-1009.
    20. Simone Schadt, Filipe Lopes, Simon Hauri, Axel Pähler, Andreas Brink. Metabolites in safety testing (MIST). 2020, 419-438.
    21. Fallon K. Noto, Valeriya Adjan-Steffey, Min Tong, Kameswaran Ravichandran, Wei Zhang, Angela Arey, Christopher B. McClain, Eric Ostertag, Sahar Mazhar, Jaya Sangodkar, Analisa DiFeo, Jack Crawford, Goutham Narla, Tseten Y. Jamling. Sprague Dawley Rag2 -Null Rats Created from Engineered Spermatogonial Stem Cells Are Immunodeficient and Permissive to Human Xenografts. Molecular Cancer Therapeutics 2018, 17 (11) , 2481-2489.
    22. Michel Leandro Campos, Letícia Bonancio Cerqueira, Bruna Cristina Ulian Silva, Taísa Busaranho Franchin, Marina Rocha Galdino-Pitta, Ivan Rocha Pitta, Rosângela Gonçalves Peccinini, Roberto Pontarolo. New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N -Substituted Thiazolidinedione. Drug Metabolism and Disposition 2018, 46 (6) , 879-887.
    23. Simone Schadt, Bojan Bister, Swapan K. Chowdhury, Christoph Funk, Cornelis E. C. A. Hop, W. Griffith Humphreys, Fumihiko Igarashi, Alexander D. James, Mark Kagan, S. Cyrus Khojasteh, Angus N. R. Nedderman, Chandra Prakash, Frank Runge, Holger Scheible, Douglas K. Spracklin, Piet Swart, Susanna Tse, Josh Yuan, R. Scott Obach. A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the “Metabolites in Safety Testing” Regulatory Guidance. Drug Metabolism and Disposition 2018, 46 (6) , 865-878.
    24. Jim Zheng, Yan Xin, Jingyu Zhang, Raju Subramanian, Bernard P. Murray, J. Andrew Whitney, Matthew R. Warr, John Ling, Lisa Moorehead, Ellen Kwan, Jeffrey Hemenway, Bill J. Smith, Jeffrey A. Silverman. Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite—Resolution for Clinical Development. Drug Metabolism and Disposition 2018, 46 (3) , 237-247.
    25. Sandeep Kumar Vishwakarma, Avinash Bardia, Chandrakala Lakkireddy, Raju Nagarapu, Md Aejaz Habeeb, Aleem Ahmed Khan. Bioengineered humanized livers as better three-dimensional drug testing model system. World Journal of Hepatology 2018, 10 (1) , 22-33.
    26. Debra Luffer-Atlas, Aisar Atrakchi. A decade of drug metabolite safety testing: industry and regulatory shared learning. Expert Opinion on Drug Metabolism & Toxicology 2017, 13 (9) , 897-900.
    27. Mika Sato-Nakai, Kosuke Kawashima, Toshito Nakagawa, Yukako Tachibana, Miyuki Yoshida, Kenji Takanashi, Peter N. Morcos, Martin Binder, David J Moore, Li Yu. Metabolites of alectinib in human: their identification and pharmacological activity. Heliyon 2017, 3 (7) , e00354.
    28. Shengyong Ng, Sandra March, Ani Galstian, Nil Gural, Kelly R. Stevens, Maria M. Mota, Sangeeta N. Bhatia. Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers. Scientific Reports 2017, 7 (1)
    29. Hidetaka Kamimura, Satoshi Ito, Hiroyuki Chijiwa, Takeshi Okuzono, Tomohiro Ishiguro, Yosuke Yamamoto, Sho Nishinoaki, Shin-Ichi Ninomiya, Marina Mitsui, Amit S. Kalgutkar, Hiroshi Yamazaki, Hiroshi Suemizu. Simulation of human plasma concentration–time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling. Xenobiotica 2017, 47 (5) , 382-393.
    30. Laurent Leclercq, Marc Bockx, Hilde Bohets, Hans Stieltjes, Vikash Sinah, Ellen Scheers. THE IMPORTANCE OF DOSE‐ AND TIME‐DEPENDENT PHARMACOKINETICS DURING EARLY METABOLITE SAFETY ASSESSMENT IN HUMANS. 2016, 293-303.
    32. I. J. Martin, S. E. Hill, J. A. Baker, S. V. Deshmukh, E. F. Mulrooney. A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose. Drug Metabolism and Disposition 2016, 44 (8) , 1435-1440.
    33. Philip Timmerman, Stefan Blech, Stephen White, Martha Green, Claude Delatour, Stuart McDougall, Geert Mannens, John Smeraglia, Stephen Williams, Graeme Young. Best Practices for Metabolite Quantification in Drug Development: Updated Recommendation from The European Bioanalysis Forum. Bioanalysis 2016, 8 (12) , 1297-1305.
    34. Balázs Klencsár, Eduardo Bolea-Fernandez, María R. Flórez, Lieve Balcaen, Filip Cuyckens, Frederic Lynen, Frank Vanhaecke. Determination of the total drug-related chlorine and bromine contents in human blood plasma using high performance liquid chromatography–tandem ICP-mass spectrometry (HPLC–ICP-MS/MS). Journal of Pharmaceutical and Biomedical Analysis 2016, 124 , 112-119.
    35. J. Iegre, M. A. Hayes, R. A. Thompson, L. Weidolf, E. M. Isin. Database Extraction of Metabolite Information of Drug Candidates: Analysis of 27 AstraZeneca Compounds with Human Absorption, Distribution, Metabolism, and Excretion Data. Drug Metabolism and Disposition 2016, 44 (5) , 732-740.
    36. Dan Xu, Gary Peltz. Can Humanized Mice Predict Drug “Behavior” in Humans?. Annual Review of Pharmacology and Toxicology 2016, 56 (1) , 323-338.
    37. Sandra March, Vyas Ramanan, Kartik Trehan, Shengyong Ng, Ani Galstian, Nil Gural, Margaret A Scull, Amir Shlomai, Maria M Mota, Heather E Fleming, Salman R Khetani, Charles M Rice, Sangeeta N Bhatia. Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens. Nature Protocols 2015, 10 (12) , 2027-2053.
    38. J. Matthew Hutzler, Barbara J. Ring, Shelby R. Anderson. Low-Turnover Drug Molecules: A Current Challenge for Drug Metabolism Scientists. Drug Metabolism and Disposition 2015, 43 (12) , 1917-1928.
    39. Thomas A. Baillie. Chemically Reactive Versus Stable Drug Metabolites: Role in Adverse Drug Reactions. 2015, 202-226.
    40. Jan Kiebist, Wolfgang Holla, Johannes Heidrich, Marzena Poraj-Kobielska, Martin Sandvoss, Reiner Simonis, Glenn Gröbe, Jens Atzrodt, Martin Hofrichter, Katrin Scheibner. One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases. Bioorganic & Medicinal Chemistry 2015, 23 (15) , 4324-4332.
    41. Ari Tolonen, Olavi Pelkonen. Analytical challenges for conducting rapid metabolism characterization for QIVIVE. Toxicology 2015, 332 , 20-29.
    42. Pei Li, Zi Li, Wayne D. Beck, Patrick M. Callahan, Alvin V. Terry, Maor Bar-Peled, Michael G. Bartlett. Bio-generation of stable isotope-labeled internal standards for absolute and relative quantitation of phase II drug metabolites in plasma samples using LC–MS/MS. Analytical and Bioanalytical Chemistry 2015, 407 (14) , 4053-4063.
    43. Makoto Niwa, Takahide Uchimura, Nozomu Koseki, Masahiro Satsukawa, Yoshitaka Hashimoto, Tsuyoshi Mayumi, Yutaka Yasuda, Hiroyuki Yokoi. Tiered Approach to Metabolite Quantification: Regional Practices Reviewed by Japan Bioanalysis Forum Discussion Group. Bioanalysis 2015, 7 (8) , 935-938.
    44. Dan Xu, Manhong Wu, Sachiko Nishimura, Toshihiko Nishimura, Sara A. Michie, Ming Zheng, Zicheng Yang, Alexander John Yates, Jeffrey S. Day, Kathleen M. Hillgren, Saori Takedai Takeda, Yuan Guan, Yingying Guo, Gary Peltz. Chimeric TK-NOG Mice: A Predictive Model for Cholestatic Human Liver Toxicity. Journal of Pharmacology and Experimental Therapeutics 2015, 352 (2) , 274-280.
    45. Theodore R. Johnson, Weiwei Tan, Lance Goulet, Evan B. Smith, Shinji Yamazaki, Gregory S. Walker, Melissa T. O’Gorman, Gabriella Bedarida, Helen Y. Zou, James G. Christensen, Leslie N. Nguyen, Zhongzhou Shen, Deepak Dalvie, Akintunde Bello, Bill J. Smith. Metabolism, excretion and pharmacokinetics of [ 14 C]crizotinib following oral administration to healthy subjects. Xenobiotica 2015, 45 (1) , 45-59.
    46. Raman Sharma, John Litchfield, Karen Atkinson, Heather Eng, Neeta B. Amin, William S. Denney, John C. Pettersen, Theunis C. Goosen, Li Di, Esther Lee, Jeffrey A. Pfefferkorn, Deepak K. Dalvie, Amit S. Kalgutkar. Metabolites in Safety Testing Assessment in Early Clinical Development: A Case Study with a Glucokinase Activator. Drug Metabolism and Disposition 2014, 42 (11) , 1926-1939.
    47. Laurent Leclercq. A Reflection on Fit-For-Purpose Metabolite Investigation at Different Stages of Drug Development. Bioanalysis 2014, 6 (5) , 591-594.
    48. Jing‐Tao Wu. The Use of Nanoelectrospray Mass Spectrometry for the Quantitation of Metabolites in the Absence of Synthetic Standards. 2014, 1-13.
    49. Ernesto Callegari, Amit S. Kalgutkar, Louis Leung, R. Scott Obach, David R. Plowchalk, Susanna Tse. Drug Metabolites as Cytochrome P450 Inhibitors: A Retrospective Analysis and Proposed Algorithm for Evaluation of the Pharmacokinetic Interaction Potential of Metabolites in Drug Discovery and Development. Drug Metabolism and Disposition 2013, 41 (12) , 2047-2055.
    50. J. J. M. A. Hendrikx, A. C. Dubbelman, H. Rosing, A. H. Schinkel, J. H. M. Schellens, J. H. Beijnen. Quantification of docetaxel and its metabolites in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry 2013, 27 (17) , 1925-1934.
    51. 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.
    52. Juefang Ding, Xiaoyan Chen, Zhiwei Gao, Xiaojian Dai, Liang Li, Cen Xie, Haoyuan Jiang, Lijia Zhang, Dafang Zhong. Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans. Drug Metabolism and Disposition 2013, 41 (6) , 1195-1210.
    53. Pei Li, Yong Gong, Heng-Keang Lim, Wenying Jian, Richard W. Edom, Rhys Salter, Jose Silva, Naidong Weng. Bio-generation of stable isotope labeled internal standards for absolute and relative quantitation of drug metabolites in plasma samples by LC–MS/MS. Journal of Chromatography B 2013, 926 , 92-100.
    54. Gary Peltz. Can ‘humanized’ mice improve drug development in the 21st century?. Trends in Pharmacological Sciences 2013, 34 (5) , 255-260.
    55. Yajing Hu, Manhong Wu, Toshihiko Nishimura, Ming Zheng, Gary Peltz. Human pharmacogenetic analysis in chimeric mice with ‘humanized livers’. Pharmacogenetics and Genomics 2013, 23 (2) , 78-83.
    56. Toshihiko Nishimura, Yajing Hu, Manhong Wu, Edward Pham, Hiroshi Suemizu, Menashe Elazar, Michael Liu, Ramazan Idilman, Cihan Yurdaydin, Peter Angus, Catherine Stedman, Brian Murphy, Jeffrey Glenn, Masato Nakamura, Tatsuji Nomura, Yuan Chen, Ming Zheng, William L. Fitch, Gary Peltz. Using Chimeric Mice with Humanized Livers to Predict Human Drug Metabolism and a Drug-Drug Interaction. Journal of Pharmacology and Experimental Therapeutics 2013, 344 (2) , 388-396.
    57. Antonia F. Stepan, Vincent Mascitti, Kevin Beaumont, Amit S. Kalgutkar. Metabolism-guided drug design. MedChemComm 2013, 4 (4) , 631.
    58. P. W. A. Howe, Z. Ament, K. Knowles, J. L. Griffin, J. Wright. Combined use of filtered and edited 1 H NMR spectroscopy to detect 13 C‐enriched compounds in complex mixtures. NMR in Biomedicine 2012, 25 (11) , 1217-1223.
    59. Ronald E. White. Review of Drug Metabolism in Drug Discovery and Development. 2012, 1-40.
    60. David C. Evans. Covalent Drug–Protein Adducts: An Exploration of Their Role in Drug‐Induced Liver and General Organ Toxicity. 2012, 1-45.
    61. Peter W. A. Howe. Fluorine–proton correlation from isolated trifluoromethyl groups using unresolved J ‐couplings. Magnetic Resonance in Chemistry 2012, 50 (10) , 705-708.
    62. Debra Luffer-Atlas. The early estimation of circulating drug metabolites in humans. Expert Opinion on Drug Metabolism & Toxicology 2012, 8 (8) , 985-997.
    63. 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.
    64. 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.
    65. Liesbeth Ceelen, Loeckie De Zwart, Marieke Voets, Vera Hillewaert, Johan Monbaliu, Greet Teuns, Werner Coussement, Tony Greway. Postmortem Redistribution of Fentanyl in the Rabbit Blood. American Journal of Forensic Medicine & Pathology 2012, 33 (2) , 119-123.
    66. Jack G. Shi, Xuejun Chen, Thomas Emm, Peggy A. Scherle, Ryan F. McGee, Yvonne Lo, Robert R. Landman, Edward G. McKeever, Naresh G. Punwani, William V. Williams, Swamy Yeleswaram. The Effect of CYP3A4 Inhibition or Induction on the Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phosphate) in Healthy Volunteers. The Journal of Clinical Pharmacology 2012, 52 (6) , 809-818.
    67. Wei Tong, Swapan Chowdhury, Mark Wrona, Kevin Bateman. Coupling of Uhplc With Fast Fraction Collection–Microplate Scintillation Counting And Ms For Radiolabeled Metabolite Profiling. Bioanalysis 2012, 4 (11) , 1299-1309.
    68. Wenying Jian, Richard W. Edom, Zhongping (john) Lin, Naidong Weng. Chromatographic Separation Methods. 2012, 381-399.
    69. Wenying Jian, Wilson Shou, Richard W. Edom, Naidong Weng, Mingshe Zhu. LC‐MS in Drug Metabolism and Pharmacokinetics: A Pharmaceutical Industry Perspective. 2012, 119-169.
    70. 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.
    71. Graham Lappin, Mark Seymour, Gerhard Gross, Martin J⊘rgensen, Morten Kall, Lisbet Kværn⊘. Meeting The Mist Regulations: Human Metabolism in Phase I Using Ams And A Tiered Bioanalytical Approach. Bioanalysis 2012, 4 (4) , 407-416.
    72. Thomas A. Baillie. Drug Metabolism in Drug Safety Evaluation. 2012, 1-24.
    73. Raju Subramanian, J. Greg Slatter. Safety Testing of Drug Metabolites: A Practical Approach for the Implementation of the MIST Guidance in PKDM. 2012, 1-17.
    74. Shelby Anderson, Debra Luffer‐Atlas, Mary Pat Knadler. Predicting Human Biotransformation Pathways. 2012, 1-27.
    75. Walter A. Korfmacher. Bioanalytical Support for Both In Vitro and In Vivo Assays Across Drug Discovery and Drug Development. 2012, 1-18.
    76. Justin D. Lutz, Nina Isoherranen. Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole. Drug Metabolism and Disposition 2012, 40 (1) , 159-168.
    77. R. Scott Obach, Angus N. Nedderman, Dennis A. Smith. Radiolabelled mass-balance excretion and metabolism studies in laboratory animals: are they still necessary?. Xenobiotica 2012, 42 (1) , 46-56.
    78. Filip Cuyckens, Nadine Pauwels, Valerie Koppen, Laurent Leclercq. Use of Relative 12 C/ 14 C Isotope Ratios to Estimate Metabolite Concentrations in The Absence of Authentic Standards. Bioanalysis 2012, 4 (2) , 143-156.
    79. Ji-Yeon Kang, So-Young Kim, Dooil Kim, Dong-Hyun Kim, Sun-Mi Shin, Sun-Ha Park, Keon-Hee Kim, Heung-Chae Jung, Jae-Gu Pan, Young Hee Joung, Youn-Tae Chi, Ho Zoon Chae, Taeho Ahn, Chul-Ho Yun. Characterization of diverse natural variants of CYP102A1 found within a species of Bacillus megaterium. AMB Express 2011, 1 (1)
    80. Graeme Smith. Are Multimetabolite Methods Fit-For-Purpose for Supporting Toxicology Studies?. Bioanalysis 2011, 3 (24) , 2701-2704.
    81. Alice A. Chen, David K. Thomas, Luvena L. Ong, Robert E. Schwartz, Todd R. Golub, Sangeeta N. Bhatia. Humanized mice with ectopic artificial liver tissues. Proceedings of the National Academy of Sciences 2011, 108 (29) , 11842-11847.
    82. Jing‐Tao Wu. Standard‐Free Estimation of Metabolite Levels Using Nanospray Mass Spectrometry: Current Statutes and Future Directions. 2011, 567-578.
    83. Gang Luo, Chuang Lu, Xinxin Ding, Donglu Zhang. Experimental Models of Drug Metabolism and Disposition. 2011, 151-196.
    84. 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.
    85. Krista Dobo, Don Walker, Andrew Teasdale. Human Genotoxic Metabolites: Identification and Risk Management. 2011, 151-167.
    86. Angus N. R. Nedderman, Don K. Walker. Metabolite Testing in Drug Development. 2011, 131-143.
    87. Gordon J Dear, Claire Beaumont, Andrew Roberts, Bianca Squillaci, Steve Thomas, Mike Nash, Donna Fraser. Approaches for The Rapid Identification of Drug Metabolites in Early Clinical Studies. Bioanalysis 2011, 3 (2) , 197-213.
    88. Baskar Nammalwar, Richard A. Bunce, Doris M. Benbrook, Tao Lu, Hui-Fang Li, Ya-Dong Chen, K. Darrell Berlin. Synthesis of N -[3,4-Dihydro-4-(acetoxymethyl)-2,2,4-trimethyl-2 H -1-benzothiopyran-6-yl]- N ′-(4-nitrophenyl)thiourea and N -[3,4-dihydro-4-(hydroxymethyl)-2,2,4-trimethyl-2 H -1-benzothiopyran-6-yl]- N ′-(4-nitrophenyl)thiourea, a Major Metabolite of N -(3,4-Dihydro-2,2,4,4-tetramethyl-2 H -1-benzothiopyran-6-YL)- N ′-(4-nitrophenyl)thiourea. Phosphorus, Sulfur, and Silicon and the Related Elements 2010, 186 (1) , 189-204.
    89. Hongying Gao, Shibing Deng, 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. Drug Metabolism and Disposition 2010, 38 (12) , 2147-2156.
    90. Hongbin Yu, Daniel Bischoff, Donald Tweedie. Challenges and solutions to metabolites in safety testing: impact of the International Conference on Harmonization M3(R2) guidance. Expert Opinion on Drug Metabolism & Toxicology 2010, 6 (12) , 1539-1549.
    91. J. Greg Slatter. Safety Testing of Drug Metabolites: Mist Guidance Impact on the Practice of Industrial Drug Metabolism. 2010, 295-312.
    92. Michael Urban, David P. Enot, Guido Dallmann, Lisa Körner, Verena Forcher, Peter Enoh, Therese Koal, Matthias Keller, Hans-Peter Deigner. Complexity and pitfalls of mass spectrometry-based targeted metabolomics in brain research. Analytical Biochemistry 2010, 406 (2) , 124-131.
    93. Sophie L. Regan, James L. Maggs, Thomas G. Hammond, Craig Lambert, Dominic P. Williams, B. Kevin Park. Acyl glucuronides: the good, the bad and the ugly. Biopharmaceutics & Drug Disposition 2010, 31 (7) , 367-395.
    94. Justin D Lutz, Yasushi Fujioka, Nina Isoherranen. Rationalization and prediction of in vivo metabolite exposures: the role of metabolite kinetics, clearance predictions and in vitro parameters. Expert Opinion on Drug Metabolism & Toxicology 2010, 6 (9) , 1095-1109.
    95. Ping Yi, Debra Luffer-Atlas. A Radiocalibration Method with Pseudo Internal Standard to Estimate Circulating Metabolite Concentrations. Bioanalysis 2010, 2 (7) , 1195-1210.
    96. Shelby Anderson, Mary Pat Knadler, Debra Luffer-Atlas. Overview of Metabolite Safety Testing from an Industry Perspective. Bioanalysis 2010, 2 (7) , 1249-1261.
    97. Angus NR Nedderman, Pat Wright. Looking Back Through the MIST: A Perspective of Evolving Strategies and Key Focus Areas for Metabolite Safety Analysis. Bioanalysis 2010, 2 (7) , 1235-1248.
    98. Janet Caceres-Cortes, Michael D Reily. NMR Spectroscopy as a Tool to Close The Gap on Metabolite Characterization Under MIST. Bioanalysis 2010, 2 (7) , 1263-1276.
    99. Graham Lappin, Mark Seymour. Addressing Metabolite Safety During First-In-Man Studies Using 14 C-Labeled Drug and Accelerator Mass Spectrometry. Bioanalysis 2010, 2 (7) , 1315-1324.
    100. Philip Timmerman, Morten Anders Kall, Ben Gordon, Sirpa Laakso, Achim Freisleben, Richard Hucker. Best Practices in a Tiered Approach to Metabolite Quantification: Views and Recommendations of The European Bioanalysis Forum. Bioanalysis 2010, 2 (7) , 1185-1194.
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