Time Course of Aldehyde Oxidase and Why It Is Nonlinear

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Armina AbbasiJeffrey P Jones

Abstract

Many promising drug candidates metabolized by aldehyde oxidase (AOX) fail during clinical trial owing to underestimation of their clearance. AOX is species-specific, which makes traditional allometric studies a poor choice for estimating human clearance. Other studies have suggested using half-life calculated by measuring substrate depletion to measure clearance. In this study, we proposed using numerical fitting to enzymatic pathways other than Michaelis-Menten (MM) to avoid missing the initial high turnover rate of product formation. Here, product formation over a 240-minute time course of six AOX substrates-O6-benzylguanine, N-(2-dimethylamino)ethyl)acridine-4-carboxamide, zaleplon, phthalazine, BIBX1382 [N8-(3-Chloro-4-fluorophenyl)-N2-(1-methyl-4-piperidinyl)-pyrimido[5,4-d]pyrimidine-2,8-diamine dihydrochloride], and zoniporide-have been provided to illustrate enzyme deactivation over time to help better understand why MM kinetics sometimes leads to underestimation of rate constants. Based on the data provided in this article, the total velocity for substrates becomes slower than the initial velocity by 3.1-, 6.5-, 2.9-, 32.2-, 2.7-, and 0.2-fold, respectively, in human expressed purified enzyme, whereas the Km remains co...Continue Reading

References

May 28, 1992·Biochemical Pharmacology·A M Stoddart, W G Levine
Jun 1, 1972·Archives of Biochemistry and Biophysics·T A KrenitskyG H Hitchings
Apr 30, 1984·Biochemical and Biophysical Research Communications·S Kitamura, K Tatsumi
Dec 1, 1984·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·B KayeW S Hillis
Feb 1, 1980·International Journal of Radiation Biology and Related Studies in Physics, Chemistry, and Medicine·A J Searle, R L Willson
May 20, 1998·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M E DolanM J Ratain
Apr 22, 1999·Biopharmaceutics & Drug Disposition·A S RosenS M Troy
Jun 15, 1999·Cancer Chemotherapy and Pharmacology·P KestellB C Baguley
Mar 20, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Matthew Hutzler, Timothy S Tracy
Dec 19, 2003·Journal of Clinical Pharmacology·R Scott ObachChristine Beedham
Mar 14, 2007·Archives of Biochemistry and Biophysics·Tapan Kumar KunduJay L Zweier
Dec 11, 2007·Cellular and Molecular Life Sciences : CMLS·E GarattiniM Terao
Jul 23, 2009·BioFactors·Ralf R Mendel
Sep 11, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Joshua F AlfaroJeffrey P Jones
Dec 31, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Deepak DalvieCho-Ming Loi
May 7, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Michael ZientekR Scott Obach
Sep 22, 2010·Journal of Medicinal Chemistry·David C PrydeThien-Duc Tran
Oct 28, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Matthew HutzlerMichael B Fisher
Feb 18, 2012·Expert Opinion on Drug Metabolism & Toxicology·Enrico Garattini, Mineko Terao
Sep 22, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·John T Barr, Jeffrey P Jones
Feb 1, 2013·Molecular Pharmaceutics·Jeffrey P Jones, Kenneth R Korzekwa
Mar 16, 2013·Chemical Research in Toxicology·Anuruddha RajapakseKent S Gates
Feb 14, 2014·Methods in Molecular Biology·John T BarrJeffrey P Jones
Oct 19, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·John T BarrMary F Paine
Mar 11, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Rachel D CrouchJ Scott Daniels
Jun 14, 2017·Biochemical Pharmacology·Keigo KonishiMiki Nakajima
Sep 11, 2017·Biochemical Pharmacology·Erickson M ParagasJeffrey P Jones
Sep 14, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jiang Wei ZhangJi Yue Jeff Zhang

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Citations

Oct 24, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·John T Rodgers, Jeffrey P Jones
Nov 17, 2020·Archives of Biochemistry and Biophysics·Bikash DangiDmitri R Davydov
Jan 13, 2021·Journal of Cheminformatics·Pranav ShahDac-Trung Nguyen
May 5, 2021·Drug Metabolism Reviews·Nikhilesh V DhuriaJasleen K Sodhi
Jun 25, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kirk D KozminskiMichael A Zientek
Jun 30, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Claudia Garrido, Silke Leimkühler
Dec 18, 2021·Pharmacology Research & Perspectives·Robert W BusbyCyril De Colle

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