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 [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 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%).

Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration

“…Bundgaard and colleagues have reported a half-life of 37.7 min for levomilnacipran administered subcutaneously in mice at a 2 mg/kg dose [ 17 ]. In contrast, another group studying this drug in rats documented a half-life of 2.3 h after oral administration at 50 mg/kg dose [ 18 ].…”

“…Curiously, there is a paucity of published studies reporting systemic and brain pharmacokinetics of milnacipran in rodents. In our literature search, we only found one article describing the pharmacokinetics of milnacipran in rats [ 16 ] and two additional articles that studied levomilnacipran [ 17 , 18 ]. Based on this, the current study was designed to study milnacipran’s systemic and brain pharmacokinetics in mice and compare IV and IP routes of administration.…”

Levomilnacipran Pharmacokinetics in Healthy Volunteers Versus Patients with Major Depressive Disorder and Implications for Norepinephrine and Serotonin Reuptake Inhibition

“…Approximately 58% of an oral dose of 14 C-levomilnacipran is excreted in the urine as unchanged levomilnacipran. 21 The primary route of metabolism of levomilnacipran is N-demethylation, 21 which is catalyzed mainly by cytochrome P450 3A4. Levomilnacipran also undergoes hydroxylation to form p-hydroxy-levomilnacipran.…”

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

“…The main metabolites excreted in urine, which are not pharmacologically active, are N-desethyllevomilnacipran (18% of the dose), levomilnacipran glucuronide (4%) and desethyllevomilnacipran glucuronide (3%). The dose should be reduced in patients with renal impairment (Brunner et al 2015), a condition which can result in increased plasma levels and prolonged t1 =2 (Chen, Greenberg, Brand-Schieber, et al 2015), while remaining generally well-tolerated (Chen et al 2014). It should also be lowered from the standard 120 mg/day to 80 mg/day or less when adjunctively used with CYP3A4 inhibitors, which is in contrast to the recommendations for milnacipran.…”