IC50: 3.4 μM (alpha-adrenergic receptor)

Absorption, Distribution and Excretion
The steady-state concentration of levomilnacipran was dose-proportional when administered at a dose ranging from 25 mg to 300 mg (2.5 times the maximum recommended dosage of levomilnacipran) once daily. After daily dosing of 120 mg levomilnacipran, the mean Cmax value was 341 ng/mL, and the mean steady-state AUC value was 5196 ng x h/mL. The relative bioavailability of oral levomilnacipran extended-release capsules was 92% when compared to oral solution. The median time to peak concentration (Tmax) of levomilnacipran ranges from six to eight hours after oral administration. Levomilnacipran concentration was not significantly affected when it was administered with food.
Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of ¹⁴C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran was the major metabolite excreted in the urine, accounting for approximately 18% of the dose. Other identifiable metabolites excreted in the urine were levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%).
Levomilnacipran is widely distributed, with an apparent volume of distribution ranging from 387 to 473 L.
Following oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h.

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Metabolism / Metabolites
Levomilnacipran undergoes desethylation to form desethyl levomilnacipran (or N-desethyl levomilnacipran) and hydroxylation to form p-hydroxy-levomilnacipran, which are pharmacologically inactive. Both oxidative metabolites can undergo further glucuronidation. Desethylation is primarily catalyzed by CYP3A4 with minor contributions by CYP2C8, 2C19, 2D6, and 2J2.

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Biological Half-Life
The apparent terminal elimination half-life of extended-release levomilnacipran is approximately 12 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Levomilnacipran has not been studied in nursing mothers. However, the racemic form of milnacipran has low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants. Until more data become available, levomilnacipran should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Monitor breastfed infants for agitation, irritability, poor feeding and poor weight gain.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Specific published information on levomilnacipran was not found as of the revision date.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking milnacipran.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

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Protein Binding
Levomilnacipran is 22% bound to plasma proteins over the concentration range of 10 to 1000 ng/mL.

[1]. Pierre Sokoloff. Levomilnacipran drug for functional rehabilitation after an acute neurological stroke. WO2013014263A1.

Levomilnacipran is a member of acetamides.
Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), although it is a more potent inhibitor of norepinephrine reuptake than serotonin reuptake. Levomilnacipran is the more active 1S,2R-enantiomer in the racemate [milnacipran]. Once administered, interconversion between levomilnacipran and its stereoisomer does not occur in humans. First approved by the FDA on July 25, 2013, levomilnacipran is used to treat major depressive disorder in adults. While levomilnacipran was previously investigated and proposed as a potential treatment for stroke in Europe, the EMA decided against this use.
Levomilnacipran is a Serotonin and Norepinephrine Reuptake Inhibitor. The mechanism of action of levomilnacipran is as a Norepinephrine Uptake Inhibitor, and Serotonin Uptake Inhibitor.
The (1S,2R)-isomer of milnacipran that is used for the treatment of MAJOR DEPRESSIVE DISORDER.
See also: Levomilnacipran Hydrochloride (active moiety of); Milnacipran (annotation moved to).

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Drug Indication
Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) in adults.
Treatment of stroke

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Mechanism of Action
Levomilnacipran is a potent and selective selective serotonin and norepinephrine reuptake inhibitor (SNRI). The exact mechanism of the antidepressant action of levomilnacipran is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system through inhibition of reuptake at serotonin and norepinephrine transporters. Like milnacipran, levomilnacipran is a more potent inhibitor of the norepinephrine transporter than the serotonin transporter: it exhibits over a 15-fold higher selectivity for norepinephrine versus serotonin reuptake inhibition.

C15H22N2O

246.35

246.173

96847-55-1

Milnacipran hydrochloride;101152-94-7;Milnacipran;92623-85-3

6917779

Colorless to light yellow liquid

1.077

393ºC at 760 mmHg

2.471

1

2

5

18

295

2

CCN(CC)C(=O)[C@@]1(C[C@@H]1CN)C2=CC=CC=C2

GJJFMKBJSRMPLA-HIFRSBDPSA-N

InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3/t13-,15+/m1/s1

(1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)