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Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2013 Sep; Vol. 41 (9), pp. 1626-41. Date of Electronic Publication: 2013 Jun 17. - Publication Year :
- 2013
-
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.
- Subjects :
- Absorption
Adult
Area Under Curve
Carbon Radioisotopes blood
Carbon Radioisotopes metabolism
Carbon Radioisotopes pharmacokinetics
Carbon Radioisotopes urine
Cytochrome P-450 Enzyme System metabolism
Feces chemistry
Half-Life
Humans
Indoles blood
Indoles urine
Male
Microsomes, Liver enzymology
Microsomes, Liver metabolism
Oxidation-Reduction
Indoles metabolism
Indoles pharmacokinetics
Receptor, Metabotropic Glutamate 5 antagonists & inhibitors
Receptor, Metabotropic Glutamate 5 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 41
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 23775850
- Full Text :
- https://doi.org/10.1124/dmd.112.050716