Pure Appl. Chem. 2021; 93(3): 273–403 IUPAC Technical Report Paul Erhardt*, Kenneth Bachmann, Donald Birkett, Michael Boberg, Nicholas Bodor, Gordon Gibson, David Hawkins, Gabrielle Hawksworth, Jack Hinson, Daniel Koehler, Brian Kress, Amarjit Luniwal, Hiroshi Masumoto, Raymond Novak, Phillip Portoghese, Jeffrey Sarver, M. Teresa Serafini, Christopher Trabbic, Nico Vermeulen and Steven Wrighton Glossary and tutorial of xenobiotic metabolism terms used during small molecule drug discovery and development (IUPAC Technical Report) https://doi.org/10.1515/pac-2018-0208 Received February 26, 2018; accepted August 20, 2019 Article note: Sponsoring bodies: IUPAC Chemistry and Human Health Division (VII) and Subcommittee on Drug Discovery and Development; Specific information is provided on page 389. Our final submission is dedicated to Gordon Gibson and Gabrielle Hawksworth, who were collegial participants on this project’s Founding Working Party. The field of drug metabolism misses them. *Corresponding author: Paul Erhardt, Center for Drug Design and Development, University of Toledo, Toledo, Ohio, USA, (TGM and ST), e-mail: [email protected] Kenneth Bachmann, Ceuticare, Inc., Sylvania, Ohio, USA, (TGM and ST) Donald Birkett, Department of Clinical Pharmacology, Flinders University, Adelaide, Australia (now Emeritus), (TGM) Michael Boberg, Metabolism and Isotope Chemistry, Bayer, AG, Germany (now undetermined), (TGM) Nicholas Bodor, Center for Drug Discovery, University of Florida, Belle Glade, FL, USA (now Emeritus Grad Res Prof/CEO Bodor Labs), (TGM) Gordon Gibson, School of Biomedical and Life Sciences, University of Surrey, Surrey, UK (now deceased), (TGM) David Hawkins, Huntingdon Life Sciences, Huntingdon, UK (now retired), (TGM) Gabrielle Hawksworth, Department of Medicine and Therapeutics, University Aberdeen, Aberdeen, UK (now deceased), (TGM) Jack Hinson, Division of Toxicology, University Arkansas for Medical Sciences, Little Rock, Arkansas, USA (now Emeritus Dist Prof), (TGM) Daniel Koehler, Department of Pharmacology, University of Toledo, Toledo, Ohio, USA, (ST) Brian Kress, Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, Ohio, USA, (ST) Amarjit Luniwal, NAmSA, Inc., Northwood, Ohio, USA, (ST) Hiroshi Masumoto, Drug Metabolism, Daiichi Pharm. Corp., Ltd., Chuo, Tokyo, Japan (now retired), (TGM) Raymond Novak, Institute of Environmental Health Science, Wayne State University,Detroit,Michigan,USA (now undetermined), (TGM) Phillip Portoghese, Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA (now same), (TGM) Jeffrey Sarver, Department of Pharmacology, University of Toledo, Toledo, Ohio, USA, (ST) M. Teresa Serafini, Department of Pharmacokinetics and Drug Metabolism, Laboratories Dr. Esteve, S.A., Barcelona, Spain (now Head Early ADME), (TGM) Christopher Trabbic, MPI Research, Inc., Mattawan, Michigan, USA, (ST) Nico Vermeulen, Department of Pharmacochemistry, Vrije University, Amsterdam, Netherlands (now Emeritus Section Molecular Toxicology), (TGM) Steven Wrighton, Eli Lilly, Inc., Indianapolis, Indiana, USA (now retired), (TGM) Task Group Member (TGM). Submission Team (ST). © 2021 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/ 274 P. Erhardt et al.: Glossary and tutorial of xenobiotic metabolism terms Abstract: This project originated more than 15 years ago with the intent to produce a glossary of drug metabolism terms having definitions especially applicable for use by practicing medicinal chemists. A first-draft version underwent extensive beta-testing that, fortuitously, engaged international audiences in a wide range of disciplines involved in drug discovery and development. It became clear that the inclusion of information to enhance discussions among this mix of participants would be even more valuable. The present version retains a chemical structure theme while expanding tutorial comments that aim to bridge the various perspectives that may arise during interdisciplinary communications about a given term. This glossary is intended to be educational for early stage researchers, as well as useful for investigators at various levels who participate on today’s highly multidisciplinary, collaborative small molecule drug discovery teams. Keywords: absorption; bioanalytical methods; biodegradation; drug delivery; drug design; drug discovery; environmental chemistry; enzyme chemistry; medicinal chemistry; metabolism; oxidation; pharmaceuticals. CONTENTS Alphabetical List of Terms ...........................................................................................................................274 Introduction .................................................................................................................................................279 Definitions with Structural Examples and Tutorials ....................................................................................282 Membership of Sponsoring Bodies, Acknowledgements ............................................................................ 389 References ....................................................................................................................................................397 Appendices ................................................................................................................................................. 390 Alphabetical List of Terms Several of the terms included in this project also appear in other IUPAC glossaries, or ‘Color Books’, such as the Red Book (2005), Blue Book (2013), and Gold Book (2014 PDF plus online version updates), wherein alternative definitions may sometimes be found due to differences in specific context or strictly intended focus. None of the present definitions are meant to displace former IUPAC recommendations, particularly when used within the context of their originating technical disciplines. Instead, the present terms and related tutorial materials are meant to enhance the discourse between technical disciplines. An alphabetical list of terms is provided below. The actual definitions follow in alphabetical order. Readers are encouraged to start with the Introduction section, soastoappreciatetheearly history and evolution of this list, and to fully relate to the finalintentofthedefinitions and their use within the overall contextoftoday’s highly interdisciplinary process for small molecule drug discovery and development. 1 ABSORPTION 2 Acetylation 3 Acetylation Phenotype 4 Active Metabolite 5 Active Transport 6 Acylation 7 Acyltransferase 8 ADME; ADMET 9 Alcohol Dehydrogenase NAD (ADH) 10 Aldehyde Dehydrogenase (ALDH) 11 Aldehyde Dehydrogenase Polymorphism or Deficiency 12 Aldehyde Oxidase (AO) 13 Allometric Scaling 14 Allosteric Regulation 15 Amino Acid Conjugation 16 Aminopeptidases P. Erhardt et al.: Glossary and tutorial of xenobiotic metabolism terms 275 17 Anabolism 18 Antibody–Drug Conjugate (ADC) 19 Apoenzyme 20 Aromatic Hydrocarbon Receptor (AHR) 21 Aromatic Hydroxylation 22 Atypical Alcohol Dehydrogenase 23 AUC (Area Under the Curve) 24 Autoinduction 25 Autoinhibition 26 BIOACTIVATION 27 Bioavailability (Absolute and Relative) 28 Bioequivalence 29 Bioinactivation 30 Biotransformation 31 Blood–Brain Barrier (BBB) 32 CARBOXYL ESTERASES (CESs) 33 Carboxypeptidases 34 Catabolism 35 Catalase and Catalase-peroxidase 36 Catechol-O-Methyl Transferase (COMT) 37 Clearance (CL) 38 Cocktail Study 39 Cofactor 40 Compartment Model 41 Competitive Inhibition 42 Conjugate 43 Conjugation Reactions 44 Covalent Binding 45 Cysteine-S-Conjugate β-Lyase (C-S Lyase) 46 Cytochrome b5 47 Cytochrome P-450 Enzymes (CYPs) 48 DEACETYLATION 49 Dealkylation 50 Deamination/Oxidative Deamination 51 Dehalogenation 52 Dehydration 53 Dehydrogenase 54 Dehydrogenation 55 Demethylation 56 Detoxification 57 Diamine Oxidases (DAO) 58 Disulfiram Reaction 59 Disposition 60 Distribution 61 DMPK 62 Dose 63 Dose-Dependent Kinetics or Metabolism 64 Drug Delivery Formulations 65 Drug–Drug Interactions 66 Drug-Like Properties or Profile 276 P. Erhardt et al.: Glossary and tutorial of xenobiotic metabolism terms 67 Drug Metabolism 68 EC NUMBER (ENZYME COMMISSION NUMBER) 69 Elimination 70 Enantioselective and Enantiospecific Metabolism 71 Endoplasmic Reticulum (ER) 72 Enterohepatic Cycling 73 Enzyme 74 Epoxidation 75 Epoxide Hydrolases 76 Esterases 77 Excretion 78 Extensive (or Rapid) Metabolizer 79 Extraction Ratio 80 Extravascular Dosing 81 FIRST PASS EFFECT/METABOLISM (PSEUDO-FIRST PASS EFFECT) 82 Flavin Monooxygenase (FMO) 83 Futile Metabolism 84 GAMMA-GLUTAMYL TRANSPEPTIDASE (γ-GLUTAMYLTRANSFERASE; GGT) 85 Genetic Polymorphism 86 Genotype/Genotyping 87 Glucocorticoid Responsive Element (GRE) 88 Glucuronic Acid Conjugation (Glucuronidation) 89 Glucuronidase (β-Glucuronidase) 90 Glucuronide 91 Glucuronosyltransferase (GT) (Previously Uridinediphosphoglucuronosyltransferase and UGT or UDPGT) 92 Glutamine Conjugation 93 Glutathione (GSH) 94 Glutathione Conjugation 95 Glutathione Transferase (GST) 96 Glycine Conjugation 97 Glycosylation (or Glycosidation) 98 Gut Microflora 99 HALF-LIFE (t1/2) 100 Hepatic Clearance/Extraction 101 Hepatocytes 102 Hepatoportal Circulation 103 Hippuric Acid Conjugate (Hippurate) 104 Holoenzyme 105 Hydrolases 106 Hydrolysis 107 Hydroxylation 108 INDUCING AGET 109 Induction 110 Inhibition 111 Intraperitoneal Dosing 112 Intravascular