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Mass Balance, Metabolism, and Excretion of Cenobamate, a New Antiepileptic Drug, After a Single Oral Administration in Healthy Male Subjects.
- Source :
-
European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2020 Aug; Vol. 45 (4), pp. 513-522. - Publication Year :
- 2020
-
Abstract
- Background and Objective: Cenobamate is an antiepileptic drug for the treatment of partial-onset seizures. The current study was designed to assess the mass balance and the metabolic profiling of cenobamate in humans.<br />Methods: Absorption, metabolism, and excretion of cenobamate were investigated in healthy male subjects after a single oral dose of 400 mg of cenobamate containing 50 µCi of [ <superscript>14</superscript> C]-cenobamate as capsule formulation.<br />Results: Cenobamate was rapidly (median time to maximum plasma concentration of 1.25 h) and extensively (≥ 88% of dose) absorbed. The mean cenobamate plasma concentration-time profile revealed a multiphasic elimination profile whereas the mean plasma/blood concentration-time curve for total radioactivity did not appear to be multiphasic, suggesting that elimination mechanisms for cenobamate and its metabolites may be different. Blood/plasma ratios observed for the area under the concentration-time curve (AUC) and peak concentration (both ~ 0.60) suggest a limited penetration of cenobamate and metabolites into red blood cells (RBCs). Eight cenobamate metabolites were identified across plasma, urine, and feces. Cenobamate was the main plasma radioactive component and M1 was the only metabolite detected in plasma (> 98% and < 2% total radioactivity AUC, respectively). All detected metabolites were found in urine, with M1 as the major radioactive component (mean cumulative recovery 37.7% of dose); unchanged cenobamate accounted for 6%. Metabolites comprised ~ 88% of the dose recovered in urine, indicating extensive metabolism by the kidneys and/or metabolites formed in the liver were rapidly eliminated from the bloodstream. However, cenobamate metabolites appear to be formed slowly. Minor amounts of cenobamate (0.48%) and five metabolites (≤ 1.75% each; M1, M3, M6, M7, M11) were recovered in feces.<br />Conclusion: This study indicates that cenobamate is primarily eliminated in urine as metabolites. Cenobamate is the major circulating component in plasma after oral administration and has a limited penetration into RBCs.
- Subjects :
- Administration, Oral
Adult
Anticonvulsants blood
Biotransformation
Carbamates blood
Chlorophenols blood
Gastrointestinal Absorption
Healthy Volunteers
Humans
Intestinal Elimination
Male
Metabolomics
Middle Aged
New Jersey
Tetrazoles blood
Young Adult
Anticonvulsants administration & dosage
Anticonvulsants pharmacokinetics
Carbamates administration & dosage
Carbamates pharmacokinetics
Chlorophenols administration & dosage
Chlorophenols pharmacokinetics
Renal Elimination
Tetrazoles administration & dosage
Tetrazoles pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 2107-0180
- Volume :
- 45
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- European journal of drug metabolism and pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 32301064
- Full Text :
- https://doi.org/10.1007/s13318-020-00615-7