Document Detail


The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5.
MedLine Citation:
PMID:  22711749     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Negative allosteric modulation (NAM) of metabotropic glutamate receptor subtype 5 (mGlu₅) represents a therapeutic strategy for the treatment of childhood developmental disorders, such as fragile X syndrome and autism. VU0409106 emerged as a lead compound within a biaryl ether series, displaying potent and selective inhibition of mGlu₅. Despite its high clearance and short half-life, VU0409106 demonstrated efficacy in rodent models of anxiety after extravascular administration. However, lack of a consistent correlation in rat between in vitro hepatic clearance and in vivo plasma clearance for the biaryl ether series prompted an investigation into the biotransformation of VU0409106 using hepatic subcellular fractions. An in vitro appraisal in rat, monkey, and human liver S9 fractions indicated that the principal pathway was NADPH-independent oxidation to metabolite M1 (+16 Da). Both raloxifene (aldehyde oxidase inhibitor) and allopurinol (xanthine oxidase inhibitor) attenuated the formation of M1, thus implicating the contribution of both molybdenum hydroxylases in the biotransformation of VU0409106. The use of ¹⁸O-labeled water in the S9 experiments confirmed the hydroxylase mechanism proposed, because ¹⁸O was incorporated into M1 (+18 Da) as well as in a secondary metabolite (M2; +36 Da), the formation of which was exclusively xanthine oxidase-mediated. This unusual dual and sequential hydroxylase metabolism was confirmed in liver S9 and hepatocytes of multiple species and correlated with in vivo data because M1 and M2 were the principal metabolites detected in rats administered VU0409106. An in vitro-in vivo correlation of predicted hepatic and plasma clearance was subsequently established for VU0409106 in rats and nonhuman primates.
Authors:
Ryan D Morrison; Anna L Blobaum; Frank W Byers; Tammy S Santomango; Thomas M Bridges; Donald Stec; Katrina A Brewer; Raymundo Sanchez-Ponce; Melany M Corlew; Roger Rush; Andrew S Felts; Jason Manka; Brittney S Bates; Daryl F Venable; Alice L Rodriguez; Carrie K Jones; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte; J Scott Daniels
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-18
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  40     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2013-01-17     Revised Date:  2013-12-10    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1834-45     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Oxidase / antagonists & inhibitors,  metabolism*
Allopurinol / pharmacology
Animals
Benzamides / administration & dosage,  blood,  chemistry,  pharmacokinetics*
Biotransformation
Chromatography, Liquid
Enzyme Inhibitors / pharmacology
Excitatory Amino Acid Antagonists / administration & dosage,  blood,  chemistry,  pharmacokinetics*
Hepatocytes / enzymology
Humans
Hydroxylation
Injections, Intravenous
Liver / drug effects,  enzymology*
Macaca fascicularis
Magnetic Resonance Spectroscopy
Male
Metabolic Clearance Rate
Microsomes, Liver / enzymology
Models, Biological
Molecular Structure
Oxygen Isotopes
Raloxifene / pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Species Specificity
Tandem Mass Spectrometry
Thiazoles / administration & dosage,  blood,  chemistry,  pharmacokinetics*
Xanthine Oxidase / antagonists & inhibitors,  metabolism*
Grant Support
ID/Acronym/Agency:
2-R01-NS31373-16/NS/NINDS NIH HHS; 5-R01-MH62646-13/MH/NIMH NIH HHS; R01 MH062646/MH/NIMH NIH HHS; R01 NS031373/NS/NINDS NIH HHS; U19 MH097056/MH/NIMH NIH HHS
Chemical
Reg. No./Substance:
0/Benzamides; 0/Enzyme Inhibitors; 0/Excitatory Amino Acid Antagonists; 0/Oxygen Isotopes; 0/Receptor, Metabotropic Glutamate 5; 0/Receptors, Metabotropic Glutamate; 0/Thiazoles; 0/VU0409106; 63CZ7GJN5I/Allopurinol; EC 1.17.3.2/Xanthine Oxidase; EC 1.2.3.1/Aldehyde Oxidase; YX9162EO3I/Raloxifene
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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