Valérie Brunner,1 Bernadette Maynadier,2 Laishun Chen,3 Louise Roques,2 Isabelle Hude,2 Sébastien Séguier,2 Laurence Barthe,1 Philippe Hermann11Pierre Fabre Médicament, Centre de R&D, Toulouse, 2Centre Experimental PreClinque, Campans, France; 3Forest Research Institute Inc., an affiliate of Actavis Inc., Jersey City, NJ, USAAbstract: Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults.We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [14C]-levomilnacipran.
In vitro binding of levomilnacipran to human plasma proteins was also studied.Unchanged levomilnacipran was the major circulating compound after dosing in all A Crítica ao Cinema Brasileiro Atual: a retórica das revistas Veja e Bravo! species.Within 12 hours of dosing in humans, levomilnacipran accounted for 52.9% of total plasma radioactivity; the circulating metabolites N-desethyl levomilnacipran N-carbamoyl glucuronide, N-desethyl levomilnacipran, and levomilnacipran N-carbamoyl glucuronide accounted for 11.
3%, 7.5%, and 5.6%, respectively.Similar results were seen in monkeys.
N-Desethyl levomilnacipran and p-hydroxy levomilnacipran were the main circulating metabolites in rats.Mass balance results indicated that renal excretion was the major route of elimination with 58.4%, 35.5%, and 40.
2% of total radioactivity being excreted as unchanged levomilnacipran in humans, monkeys, and rats, respectively.N-Desethyl levomilnacipran was detected in human, monkey, and rat urine (18.2%, 12.4%, and 7.
9% of administered dose, respectively).Human and Optimization of Communication Schemes for DMA-Controlled Accelerators monkey urine contained measurable quantities of levomilnacipran glucuronide (3.8% and 4.1% of administered dose, respectively) and N-desethyl levomilnacipran glucuronide (3.
2% and 2.3% of administered dose, respectively); these metabolites were not detected in rat urine.The metabolites p-hydroxy levomilnacipran and p-hydroxy levomilnacipran glucuronide were detected in human urine (≤1.2% of administered dose), and p-hydroxy levomilnacipran glucuronide was found in rat urine (4% of administered dose).
None of the metabolites were pharmacologically active.Levomilnacipran was widely distributed with low plasma protein binding (22%).Keywords: FETZIMA, metabolites, mass balance, excretion, tissue distribution.