title: Disposition and metabolism of [14C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats.
abstract: 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 [(14)C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins was also studied. Unchanged levomilnacipran was the major circulating compound after dosing in all 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 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%).
authors.affiliation: Pierre Fabre Médicament, Centre de R&D, Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Brunner
authors.affiliation: Centre Experimental PreClinque, Campans, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Maynadier
authors.affiliation: Forest Research Institute Inc., an affiliate of Actavis Inc., Jersey City, NJ, USA.
authors.forename: Laishun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Centre Experimental PreClinque, Campans, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Roques
authors.affiliation: Centre Experimental PreClinque, Campans, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hude
authors.affiliation: Centre Experimental PreClinque, Campans, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Séguier
authors.affiliation: Pierre Fabre Médicament, Centre de R&D, Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Barthe
authors.affiliation: Pierre Fabre Médicament, Centre de R&D, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hermann
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D002250:Carbon Radioisotopes; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003640:Dealkylation; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D006900:Hydroxylation; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D008954:Models, Biological; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013045:Species Specificity; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D002250:Carbon Radioisotopes; D003521:Cyclopropanes; D020719:Glucuronides; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000078764:Milnacipran
keywords: FETZIMA; excretion; mass balance; metabolites; tissue distribution