Abstract
This study was designed to investigate the human absorption, disposition, and mass balance of 14C-brivaracetam, a novel high affinity SV2A ligand with potent anticonvulsant activity. Six healthy male subjects received a single p.o. dose of 14C-brivaracetam (150 mg, 82 μCi, or 3.03 MBq). Serial blood and complete urine and feces were collected until 144 h postdose. Expired air samples were obtained until 24 h. Brivaracetam was rapidly absorbed, with Cmax of 4 μg/ml occurring within 1.5 h of dosing. Unchanged brivaracetam amounted to 90% of the total plasma radioactivity, suggesting a modest first-pass effect. Plasma protein binding of radioactivity was low (17.5%). Urinary excretion exceeded 90% after 2 days, and the final mass balance reached 96.8% of the radioactivity in urine and 0.7% in feces. Only 8.6% of the radioactive dose was recovered in urine as unchanged brivaracetam, the remainder being identified as non–cytochrome P450 (P450)- and P450-dependent biotransformation products resulting from hydrolysis of the amide moiety (M9, 34.2%), hydroxylation of the n-propyl side chain (M1b, 15.9%), and a combination of these two pathways leading to the hydroxy acid (M4b, 15.2%). Minor amounts of taurine and glucuronic acid conjugates and other oxidized derivatives were also identified. Brivaracetam is completely absorbed, is weakly bound to plasma proteins, extensively biotransformed through several metabolic pathways, and eliminated renally.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.017129.
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ABBREVIATIONS: Brivaracetam, (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl] butanamide; HPLC, high-performance liquid chromatography; Ht, hematocrit; MS, mass spectrometry; TFA, trifluoroacetic acid; MDA, minimum detectable activity; CID, collision-induced dissociation; AUC0-t, area under the plasma concentration-time curve from time of dosing to time of last measurable concentration; AUC, area under the plasma concentration-time curve; COSY, correlation spectroscopy; P450, cytochrome P450.
- Received July 9, 2007.
- Accepted September 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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