title: Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects.
abstract: The disposition and biotransformation of (14)C-radiolabeled mavoglurant were investigated in four healthy male subjects after a single oral dose of 200 mg. Blood, plasma, urine, and feces collected over 7 days were analyzed for total radioactivity, mavoglurant was quantified in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and metabolite profiles were generated in plasma and excreta by high-performance liquid chromatography (HPLC) and radioactivity detection. The chemical structures of mavoglurant metabolites were characterized by LC-MS/MS, wet-chemical and enzymatic methods, NMR spectroscopy, and comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ≥50% of dose reaching mean plasma Cmax values of 140 ng/ml (mavoglurant) and 855 ng-eq/ml (total radioactivity) at 2.5 and 3.6 hours, respectively. Thereafter, mavoglurant and total radioactivity concentrations declined with mean apparent half-lives of 12 and 18 hours, respectively. The elimination of mavoglurant occurred predominantly by oxidative metabolism involving primarily 1) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and 2) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to mavoglurant and seven main metabolites, which combined accounted for 60% of (14)C-AUC0-72 h (area under the concentration-time curve from time 0 to infinity). The primary steps of mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant cytochrome P450 enzymes. After 7 days, the mean balance of total radioactivity excretion was almost complete (95.3% of dose) with 36.7% recovered in urine and 58.6% in feces.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland. markus.walles@novartis.com
authors.forename: Markus
authors.initials: M
authors.lastname: Walles
authors.forename: Thierry
authors.initials: T
authors.lastname: Wolf
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Michael
authors.initials: M
authors.lastname: Ritzau
authors.forename: Luc Alexis
authors.initials: LA
authors.lastname: Leuthold
authors.forename: Joel
authors.initials: J
authors.lastname: Krauser
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gschwind
authors.forename: David
authors.initials: D
authors.lastname: Carcache
authors.forename: Matthias
authors.initials: M
authors.lastname: Kittelmann
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ocwieja
authors.forename: Mike
authors.initials: M
authors.lastname: Ufer
authors.forename: Ralph
authors.initials: R
authors.lastname: Woessner
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Piet
authors.initials: P
authors.lastname: Swart
mesh_terms: D000042:Absorption; D000328:Adult; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; C578935:GRM5 protein, human; D007211:Indoles; D064529:Receptor, Metabotropic Glutamate 5; D003577:Cytochrome P-450 Enzyme System; C581397:mavoglurant