The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5.
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.
Drug Metabolism and Pharmacokinetics, Vanderbilt Center for Neurosciences Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
Ryan D
RD
Morrison
Anna L
AL
Blobaum
Frank W
FW
Byers
Tammy S
TS
Santomango
Thomas M
TM
Bridges
Donald
D
Stec
Katrina A
KA
Brewer
Raymundo
R
Sanchez-Ponce
Melany M
MM
Corlew
Roger
R
Rush
Andrew S
AS
Felts
Jason
J
Manka
Brittney S
BS
Bates
Daryl F
DF
Venable
Alice L
AL
Rodriguez
Carrie K
CK
Jones
Colleen M
CM
Niswender
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
Kyle A
KA
Emmitte
J Scott
JS
Daniels
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001711:Biotransformation; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology; D008954:Models, Biological; D015394:Molecular Structure; D010103:Oxygen Isotopes; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001549:Benzamides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010103:Oxygen Isotopes; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C577470:VU0409106; D020849:Raloxifene Hydrochloride; D000493:Allopurinol; D014969:Xanthine Oxidase; D042931:Aldehyde Oxidase