RT Journal Article
SR Electronic
T1 Metabolism and Disposition of the Metabotropic Glutamate Receptor 5 Antagonist (mGluR5) Mavoglurant (AFQ056) in Healthy Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1626
OP 1641
DO 10.1124/dmd.112.050716
VO 41
IS 9
A1 Markus Walles
A1 Thierry Wolf
A1 Yi Jin
A1 Michael Ritzau
A1 Luc Alexis Leuthold
A1 Joel Krauser
A1 Hans-Peter Gschwind
A1 David Carcache
A1 Matthias Kittelmann
A1 Magdalena Ocwieja
A1 Mike Ufer
A1 Ralph Woessner
A1 Abhijit Chakraborty
A1 Piet Swart
YR 2013
UL http://dmd.aspetjournals.org/content/41/9/1626.abstract
AB The disposition and biotransformation of 14C-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 14C-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.