Structural alerts, reactive metabolites, and protein covalent binding: how reliable are these attributes as predictors of drug toxicity?

Chemistry & Biodiversity
Amit S Kalgutkar, Mary T Didiuk

Abstract

In an increasing number of cases, a deeper understanding of the biochemical basis for idiosyncratic adverse drug reactions (IADRs) has aided to replace a vague perception of a chemical class effect with a sharper picture of individual molecular peculiarity. Considering that IADRs are too complex to duplicate in a test tube, and their idiosyncratic nature precludes prospective clinical studies, it is currently impossible to predict which new drugs will be associated with a significant incidence of toxicity. Because it is now widely appreciated that reactive metabolites, as opposed to the parent molecules from which they are derived, are responsible for the pathogenesis of some IADRs, the propensity of drug candidates to form reactive metabolites is generally considered a liability. Procedures have been implemented to monitor reactive-metabolite formation in discovery with the ultimate goal of eliminating or minimizing the liability via rational structural modification of the problematic chemical series. While such mechanistic studies have provided retrospective insight into the metabolic pathways which lead to reactive metabolite formation with toxic compounds, their ability to accurately predict the IADR potential of new drug c...Continue Reading

References

Jul 1, 1991·British Journal of Industrial Medicine·A Yardley-JonesD V Parke
Jan 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·H SatohL R Pohl
Sep 1, 1971·The Journal of Antibiotics·E S Wagner, M Gorman
Mar 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·D C DahlinS D Nelson
Jun 1, 1993·Biological Mass Spectrometry·T A Baillie, M R Davis
Dec 1, 1995·Journal of Clinical Psychopharmacology·D S GreeneR H Barbhaiya
Oct 1, 1996·Chemical Research in Toxicology·M BourdiL R Pohl
Dec 1, 1996·Annals of Internal Medicine·J C Almeida, E W Grimsley
Jun 1, 1997·Chemical Research in Toxicology·I M RietjensP J van Bladeren
Jun 1, 1997·European Journal of Immunology·E PadovanH U Weltzien
May 2, 1997·Chemico-biological Interactions·J UetrechtS Rakhit
Oct 29, 1997·Clinical Pharmacokinetics·D S Greene, R H Barbhaiya
Jul 8, 1998·Lancet·D Schmassmann-SuhijarW E Haefeli
Oct 3, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·D A HessM J Rieder
Dec 3, 1999·British Journal of Clinical Pharmacology·K JorgaR Gasser
Oct 13, 2000·Regulatory Toxicology and Pharmacology : RTP·H OlsonA Heller
Mar 22, 2002·The Journal of Pharmacology and Experimental Therapeutics·Hsia-lien LinPaul F Hollenberg
Apr 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Thomayant PrueksaritanontThomas A Baillie
May 1, 2002·JAMA : the Journal of the American Medical Association·Karen E LasserDavid H Bor
May 23, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Daniel C KempJeffrey C Stevens
May 25, 2002·Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie·Donna E Stewart
Jul 26, 2002·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Nicholas A Buckley, Jayasri Srinivasan
Oct 18, 2002·CNS Drugs·Yadhu N Singh, Nirbhay N Singh
Oct 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·James M MathewsSherry R Black
Feb 7, 2003·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·Z ZhaoJ Rimmer
Feb 18, 2003·Chemical Research in Toxicology·Kirsten S SmithTimothy L Macdonald
Jun 17, 2003·Chemical Research in Toxicology·Benjamin M JohnsonRichard B van Breemen
Jun 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Donglu ZhangJames Mitroka
Sep 19, 2003·Journal of Computer-aided Molecular Design·John C Dearden
Feb 27, 2004·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Neil Kaplowitz
Apr 8, 2004·Toxicology Letters·Dallas L Clouatre
May 25, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kan HeThomas F Woolf
Aug 3, 2004·Nature Reviews. Drug Discovery·Ismail Kola, John Landis
Oct 27, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Donglu ZhangLewis J Klunk
Nov 4, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Amit S KalgutkarCornelis E C A Hop
Jan 8, 2005·Clinical Pharmacology and Therapeutics·Barbara J RingDiane L Phillips
Apr 2, 2005·Clinics in Dermatology·Ronni WolfHagit Matz
Jun 25, 2005·Current Drug Metabolism·Amit S KalgutkarShawn P Harriman
Oct 28, 2005·Journal of Medicinal Chemistry·Gabriele CrucianiRiccardo Vianello
Dec 24, 2005·Expert Opinion on Drug Safety·Rebeca Rodriguez-PenaMaria Jose Torres

❮ Previous
Next ❯

Citations

Nov 19, 2010·Bioanalysis·Dennis A Smith, R Scott Obach
Oct 19, 2011·Future Medicinal Chemistry·Seetharama D Satyanarayanajois, Ronald A Hill
Oct 29, 2011·Expert Opinion on Drug Metabolism & Toxicology·Claire M EllisonMark T D Cronin
Apr 20, 2011·Expert Opinion on Drug Metabolism & Toxicology·Mona Arab-AlameddineChantal Csajka
Nov 21, 2014·Drug Metabolism Reviews·Deepak DalvieWeichao Chen
Feb 7, 2012·Drug Discovery Today·Bernard TestaGiulio Vistoli
Jan 18, 2011·Chemico-biological Interactions·W Griffith Humphreys
May 11, 2016·ACS Central Science·Tyler B HughesS Joshua Swamidass
Dec 23, 2015·Journal of Applied Toxicology : JAT·M José Gómez-LechónM Teresa Donato
Nov 26, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Christine M Hunt
Apr 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Nagsen GautamYazen Alnouti
Mar 31, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Li-Na HeXin He
Mar 6, 2015·Chemical Research in Toxicology·Tyler B HughesS Joshua Swamidass
Apr 22, 2016·Chemical Research in Toxicology·David Jonathan EbbrellSteven J Enoch
Mar 5, 2015·European Journal of Drug Metabolism and Pharmacokinetics·Xing-Jie LiuBen-Kang Shi
Aug 3, 2014·International Journal of Psychiatry in Medicine·Han-Ching Tang, Kuo-Hsuan Chung
Aug 2, 2016·Mutation Research. Genetic Toxicology and Environmental Mutagenesis·Bernardo Brito PalmaMichel Kranendonk
Oct 12, 2013·Chemical Research in Toxicology·Kevin J Schneider, Anthony P DeCaprio
Apr 22, 2011·Chemical Research in Toxicology·Line R OlsenChristian Skonberg
Apr 18, 2012·Chemical Research in Toxicology·Xiaohai Li, Michael D Cameron
Sep 30, 2016·The Journal of Physical Chemistry. a·Kudzanai ChipisoReuben H Simoyi
Jan 25, 2017·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Xin LiLianshan Zhang
Mar 4, 2017·Chemical Research in Toxicology·Na Le DangS Joshua Swamidass
Sep 28, 2016·Expert Opinion on Drug Metabolism & Toxicology·M José Gómez-LechónM Teresa Donato
Jul 21, 2017·International Journal of Molecular Sciences·Jasleen K SodhiS Cyrus Khojasteh
Oct 1, 2011·Nature Reviews. Drug Discovery·Paul D Leeson, Stephen A St-Gallay
Nov 4, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Cecilia RenzulliGary Boyle
Jun 10, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yiding HuDavid C Thompson
Jul 10, 2020·Drug Metabolism Reviews·Chaitanya K JaladankiPrasad V Bharatam
Jun 12, 2020·Journal of Chemical Information and Modeling·Noah R FlynnS Joshua Swamidass
Sep 4, 2020·Journal of Chemical Information and Modeling·Tyler B HughesS Joshua Swamidass
Apr 27, 2021·Chemical Research in Toxicology·Chaitanya K JaladankiPrasad V Bharatam
Jun 12, 2020·Chemical Research in Toxicology·Markus WallesPeter End
Jan 23, 2018·Chemical Research in Toxicology·Na Le DangS Joshua Swamidass
Jan 5, 2018·Journal of Medicinal Chemistry·David W PiotrowskiJonathan Bauman

❮ Previous
Next ❯

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