Absorption, Distribution and Excretion
After oral administration, the absolute bioavailability of racemic mirtazapine is approximately 85-90%. Maximum plasma concentrations are reached within 2-4 hours after oral administration, and steady-state plasma concentrations are reached within 36-48 hours. In contrast, the relative bioavailability of levomirtazapine has been confirmed at 92%. The median time to peak concentration (Tmax) of levomirtazapine is 6-8 hours after oral administration. After daily administration of 120 mg levomirtazapine, the mean Cmax is 341 ng/mL, and the mean steady-state AUC is 5196 ng·h/mL. Generally, taking racemic mirtazapine or levomirtazapine with food does not affect the oral bioavailability of the drug. Levomirtazapine and its metabolites are primarily excreted by the kidneys. Following oral administration of 14C-levomirnacitabine solution, approximately 58% of the dose is excreted unchanged in the urine. N-Desethyllevomirnacitabine is the major metabolite excreted in the urine, accounting for approximately 18% of the dose. Other identifiable metabolites excreted in the urine include levomirnacitabine glucoside (4%), desethyllevomirnacitabine glucoside (3%), p-hydroxylevomirnacitabine glucoside (1%), and p-hydroxylevomirnacitabine (1%). The mean volume of distribution recorded after a single intravenous injection of racemic mirnacitabine in healthy subjects was approximately 400 L. Levomirnacitabine is widely distributed, with an apparent volume of distribution of 387–473 L. The total plasma clearance of mirnacitabine is approximately 40 L/h.

---

Metabolism/Metabolites
Levomirnacitabine has been identified to yield deethylated levmirnacitabine and p-hydroxylated levmirnacitabine via deethylation and hydroxylation, respectively. Both oxidative metabolites further conjugate with glucuronide to form the conjugate mirnacitabine carbamoyl-O-glucuronide. Deethylation is primarily catalyzed by CYP3A4, with minor contributions from CYP2C8, 2C19, 2D6, and 2J2. Furthermore, it is generally accepted that the enantiomers of mirnacitabine do not interconvert in vivo.

---

Biological Half-Life
The recorded terminal elimination half-life of racemic mirnacitabine is approximately 6–8 hours, while that of d-mirnacitabine is 8–10 hours, longer than the 4–6 hours of the l-enantiomer. Alternatively, the terminal elimination half-life determined specifically for levnacitabine formulations is approximately 12 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Milaprom levels in breast milk are very low and are not expected to have any adverse effects on breastfed infants. However, breastfeeding women should use mirtazaprom with caution, especially when breastfeeding newborns or premature infants, until more data become available.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
According to the manufacturer, galactorrhea is one of the side effects of mirtazaprom. A woman undergoing treatment for depression intentionally overdosed 950 mg of mirtazaprom. From day 5 to day 15 after the overdose, the patient noticed milk leakage from her left breast. The galactorrhea resolved spontaneously without treatment.
A study of cases of hyperprolactinemia and its symptoms (such as gynecomastia) reported by the French National Center for Drug Vigilance found that mirtazaprom did not increase the risk of hyperprolactinemia compared to other drugs.
An observational study investigated the outcomes of 2,859 women who took antidepressants in the two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants in all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in the third trimester were 75% less likely to breastfeed at discharge. Mothers who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. The specific antidepressants used by the mothers were not specified.
A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women who took antidepressants in the third trimester (n = 575), women with mental illness but not taking antidepressants (n = 1,552), and mothers who were not diagnosed with mental illness (n = 30,535). The results showed that women who took antidepressants were 37% less likely to breastfeed at discharge than women who were not diagnosed with mental illness, but there was no significant difference in the likelihood of breastfeeding compared to mothers with untreated mental illness. None of the mothers took mirtazapine. A study of 80,882 Norwegian mother-infant pairs between 1999 and 2008 showed that 392 women reported starting antidepressants postpartum, and another 201 women reported starting antidepressants during pregnancy. Compared to the control group without antidepressant exposure, antidepressant use in late pregnancy was associated with a 7% lower rate of breastfeeding initiation, but had no effect on the duration of breastfeeding or exclusive breastfeeding rate. Compared to the control group without antidepressant exposure, starting or restarting antidepressant use postpartum was associated with a 63% lower rate of breastfeeding as the primary breastfeeding at 6 months, a 51% lower rate of any form of breastfeeding, and a 2.6-fold increased risk of abrupt cessation of breastfeeding. No specific antidepressant was mentioned. Protein Binding: Racemic mirtazapine has a protein binding rate of 13%. In contrast, levamisole has a plasma protein binding rate of 22% in the concentration range of 10 to 1000 ng/mL.

[1]. Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985 Dec;24(12):1211-9.

[2]. Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol. 1996 Sep;11 Suppl 4:9-14.

Pharmacodynamics
In the treatment of fibromyalgia, a double-blind, placebo-controlled, and positive-controlled parallel study measured the effect of mirtazapine on the QTcF interval in patients. The study included 88 healthy subjects using 3 to 6 times the recommended dose for fibromyalgia (600 mg/day). After baseline and placebo correction, the maximum mean change in QTcF interval was 8 milliseconds—an increase typically considered clinically insignificant. Conversely, in the treatment of major depressive disorder (MDD), non-clinical studies have shown that levamisole binds with high affinity to norepinephrine (NE) and serotonin (5-HT) transporters (Ki values of 71–91 nM and 11 nM, respectively, on human transporters). Levomirnacitabine inhibits the uptake of both NE and 5-HT both in vitro and in vivo; its inhibitory effect on norepinephrine (NE) reuptake is approximately twice that of serotonin (5-HT). Levomirnacitabine does not directly affect the uptake of dopamine or other neurotransmitters. In vitro studies have shown that levomirnacitabine has no significant affinity for serotonergic receptors (5-HT1-7), α- and β-adrenergic receptors, muscarinic receptors (M1-5), histamine receptors (H1-4), dopamine receptors (D1-5), opioid receptors, benzodiazepine receptors, and γ-aminobutyric acid (GABA) receptors. Levomirnacitabine also has no significant affinity for Ca++, K+, Na+, and Cl- channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase. Furthermore, in electrocardiographic studies of levomirnacitabine in the treatment of major depressive disorder (MDD), although no clinically significant changes in the QTcF interval (QTcF = QT/RR 0.33) were observed, the drug appears to cause increases in heart rate and blood pressure. In particular, the maximum therapeutic dose of 120 mg levomilacromide daily appeared to increase heart rate by a mean of 20.2 beats/min compared to the placebo group, and increase systolic and diastolic blood pressure by a mean of 3.8 to 7.2 mmHg and 6.1 to 8.1 mmHg, respectively. Alternatively, a supertherapeutic dose of 300 mg daily resulted in a mean maximum difference of 22.1 beats/min in heart rate compared to placebo, and mean differences of 5.4 to 7.9 mmHg in systolic and 7.9 to 10.6 mmHg, respectively.

C15H22N2O

246.34798

246.173

92623-85-3

Milnacipran hydrochloride;101152-94-7;Milnacipran ((1S-cis) hydrochloride);175131-60-9;Dextromilnacipran;96847-55-1;Milnacipran-d10 hydrochloride;1217774-40-7

65833

Typically exists as solid at room temperature

1.1±0.1 g/cm3

393.0±21.0 °C at 760 mmHg

228-228.5ºC

191.5±22.1 °C

0.0±0.9 mmHg at 25°C

1.554

1.23

1

2

5

18

295

2

C([C@@]1(C[C@@H]1CN)C1C=CC=CC=1)(=O)N(CC)CC

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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