Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition

Molecular Pharmacology
Cheng ChangTristan S Maurer

Abstract

Kynurenic acid (KYNA) plays a significant role in maintaining normal brain function, and abnormalities in KYNA levels have been associated with various central nervous system disorders. Confirmation of its causality in human diseases requires safe and effective modulation of central KYNA levels in the clinic. The kynurenine aminotransferases (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16-76 hours' half-life (t1/2)], whereas KYNA is cleared more rapidly from the brain (<1 hour t1/2) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours t1/2, respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (∼80%) ...Continue Reading

References

Aug 1, 1993·Journal of Pharmacokinetics and Biopharmaceutics·N L DaynekaW J Jusko
Nov 19, 1997·Journal of Neuroscience Research·P GuidettiR Schwarcz
Oct 16, 2001·Biological Psychiatry·R SchwarczR C Roberts
Jan 24, 2003·Journal of Neural Transmission·C KissR Schwarcz
Mar 6, 2004·Journal of Pharmacokinetics and Pharmacodynamics·Liping ZhangLewis B Sheiner
Dec 2, 2005·Journal of Pharmacokinetics and Pharmacodynamics·Matthew M HutmacherDavid C Jordan
Feb 24, 2006·Trends in Pharmacological Sciences·Trevor W Robbins, Emily R Murphy
Oct 28, 2006·Annual Review of Pharmacology and Toxicology·Meindert DanhofRob A Voskuyl
Apr 20, 2007·Journal of Neurochemistry·Paolo GuidettiRobert Schwarcz
Dec 7, 2007·The Journal of Biological Chemistry·Franca RossiMenico Rizzi
May 24, 2008·Glycobiology·Brian P Rempel, Stephen G Withers
Feb 20, 2009·Journal of Neurochemistry·Laura AmoriRobert Schwarcz
Oct 15, 2009·Cellular and Molecular Life Sciences : CMLS·Qian HanJianyong Li
Nov 10, 2009·Methods in Enzymology·Petr Kuzmič
Jan 29, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Brett C DiNataleGary H Perdew
Apr 28, 2010·Journal of Psychiatry & Neuroscience : JPN·Sara K OlssonMikael Landén
Mar 29, 2011·The FEBS Journal·Elisabetta PasseraAndrea Mozzarelli
Mar 15, 2012·The Journal of Pharmacology and Experimental Therapeutics·Kenneth T LuuEugenia Kraynov
Sep 29, 2012·Journal of Pharmaceutical Sciences·Liang ZhaoChandrahas G Sahajwalla
Dec 19, 2013·Proceedings of the National Academy of Sciences of the United States of America·Phillip A SchwartzBrion William Murray
Mar 8, 2012·ACS Medicinal Chemistry Letters·Amy B DounayPatrick R Verhoest
Jan 10, 2013·ACS Medicinal Chemistry Letters·Jamison B TuttlePatrick R Verhoest
Aug 8, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Rouba KozakStacy A Castner
Oct 31, 2015·Neuropharmacology·Klas R LinderholmGöran Engberg

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Citations

Mar 16, 2019·Frontiers in Molecular Biosciences·Franca RossiMenico Rizzi
Jan 9, 2020·Journal of Medicinal Chemistry·Tristan S MaurerLi Di

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