α2-adrenergic receptor ( pKi = 6.95 ); 5-HT₃ Receptor ( pKi = 8.1 ); 5-HT₂ Receptor ( pKi = 8.05 ); H₁ Receptor ( pKi = 9.3 )

Mirtazapine (1-20 mg/kg; intraperitoneal injection; once; C57BL/6 mice) treatment dramatically and dose-dependently prevents liver damage caused by Con A[3]. Mirtazapine treatment inhibits the activation of hepatic macrophages and monocytes, reduces the production of pro-inflammatory cytokines (e.g., TNFα) and chemokines (e.g., CXCL1 and CXCL2) by hepatic macrophages and monocytes, and suppresses the increases in hepatic expression of the neutrophil relevant endothelial cell adhesion molecule ICAM-1 induced by Con A. These actions lead to a significant reduction in the recruitment of neutrophils into the liver[3].

The neurochemical and autonomic pharmacological profile of 1,2,3,4,10, 14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c]pyrido[2, 3-c] [2] benzazepine [+/-)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H]noradrenaline ([3H]NA) in vitro was weakly affected by (+/-)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (+/-)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by alpha 2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (-)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosin to alpha 1-adrenoceptors was less potently affected by (+/-)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for alpha 1- and alpha 2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (+/-)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (+/-)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (+/-)Org 3770 (pKi = 6.1) and mianserin (pKi = 6.3). Similar data on tryptamine-D, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA[2].

Mirtazapine Effects on Cytokine/Chemokine Production by Human Monocytes and CD4 T Cells in vitro[3]
CD14+ monocytes were isolated from healthy donor peripheral blood using an autoMACS Separator and autoMACS CD14+ positive selection kit. CD14+ cells were seeded into 24-well tissue culture plates (density of 1 × 106 cells/well) in 500 μl RPMI 1,640 medium supplemented with 10% FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, and 100 units/ml penicillin and streptomycin, and non-essential amino acids (NEAA). After 4 h incubation (5% CO2, 37°C) non-adherent cells were removed by washing, and 500 μl of pre-warmed complete fresh media added to wells. Designated wells were treated with mirtazapine (10 μM) or vehicle (0.2 μl/ml DMSO). One hour later Con A (5 μg/ml) or vehicle were added to designated wells, and cells cultured for another 24 h. Supernatants were collected and stored at −80°C until assayed for cytokine/chemokine levels (expressed as pg/ml).
CD4+ T cells were isolated from healthy donor peripheral blood using EasySep™ Human CD4+ T cell isolation kit. Purity of isolated cells as tested by flow cytometry was >97%. Cells were cultured in a 24-well plate (density 106 cells/well) in 500 μl RPMI 1,640 medium supplemented with 10% FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, and 100 units/ml penicillin and streptomycin, and non-essential amino acids (NEAA). Designated wells were treated with mirtazapine (10 μM) or vehicle (0.2 μl/ml DMSO). One hour later Con A (5 μg/ml) or vehicle were added to designated wells, and cells cultured for another 24 h. Supernatants were collected and stored at −80°C until assayed for cytokine levels. Human IL-10, IL-4, and IFNγ were measured in culture supernatants using a human MILLIPLEX kit according to the manufacturer's protocol. The multiplexing analysis was performed using the Luminex 100 system

Male C57BL/6 mice (8-10 week old) treated with concanavalin A (Con A)
1 mg/kg, 10 mg/kg, and 20 mg/kg
Intraperitoneal injection; once

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Mirtazapine Treatment and Con A Hepatitis Severity[3]
To delineate the impact of mirtazapine treatment in Con A hepatitis, mice were treated 1 h prior to Con A treatment with mirtazapine 1–20 mg/kg intraperitoneally (ip). Blood and liver samples were collected under isoflurane anesthesia 16 h post-Con A treatment (unless otherwise noted) to assess liver injury biochemically (plasma alanine aminotransferase [ALT] activity; measured using Roche-Hitachi Modular-P800 apparatus) and histologically using formalin-fixed liver tissue slices stained with Hematoxylin and Eosin (H&E). Extent of liver parenchymal necrosis was quantitated as previously described using Image J software and an Olympus XC10 camera (acquired using the Olympus VS-ASW software package; original magnification x400). In additional experiments, mirtazapine (20 mg/kg ip) was administered 2 h after Con A treatment (i.e., therapeutically) and mice sacrificed 16 h later and severity of liver injury determined by ALT measurement. In further experiments, the impact of specifically blocking individual receptors known to be impacted by mirtazapine treatment (i.e., 5HT2a, 5HT2c, 5HT3, and H1; also 5HT1a receptor) on the severity of Con A hepatitis was determined by ALT measurement.

Absorption, Distribution and Excretion
The absorption of this drug is rapid and complete. Due to first pass metabolism in the liver and metabolism in the gut wall, absolute bioavailability is about 50%. Peak blood concentrations are attained within about 2 hours after an oral dose. Food has little effect on the absorption of mirtazapine, and no dose adjustment is required if it is taken with food. Steady-state levels are achieved by about 5 days after the initial dose. Mirtazapine pharmacokinetics vary across gender and age range. Females and the elderly population have been shown to have higher blood concentrations in comparison to males and younger adults.
This drug is mainly excreted by the kidney. It is 75% eliminated in the urine and 15% eliminated in the feces.
The volume of distribution after an oral steady-state dose was measured to be 107 ± 42L in a pharmacokinetic study.
Total body clearance in males was found to be 31 L/h in a clinical pharmacokinetics study after intravenous administration. **Clearance in elderly patients*
Mirtazapine clearance is slower in the elderly than in younger subjects. Exercise caution when this drug is given to elderly patients. In a clinical trial, elderly males showed a marked decrease in mirtazapine clearance when compared to young males taking the same dose. This difference was less significant when clearance was compared between elderly females and younger females taking mirtazapine. **Clearance in hepatic and renal impairment** Patients with hepatic and renal impairment have decreased rates of clearance and dosage adjustments may be necessary for these patients. Moderate renal impairment and hepatic impairment cause about a 30% decrease in mirtazapine clearance. Severe renal impairment leads to a 50% decrease in mirtazapine clearance.

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Metabolism / Metabolites
Mirtazapine is heavily metabolized in humans. Demethylation and hydroxylation and subsequent glucuronide conjugation are the major pathways by which mirtazapine is metabolized. Data from in vitro studies on human liver microsomes show that cytochrome 2D6 and 1A2 lead to the formation of the _8-hydroxy metabolite_ of mirtazapine. The CYP3A enzyme metabolizes this drug into its _N-desmethyl and N-oxide_ metabolites. There are various other unconjugated metabolites of this drug that are pharmacologically active, but are measured in the blood at limited concentrations.
Mirtazapine has known human metabolites that include Mirtazapine N-oxide, N-Desmethylmirtazapine, and 8-hydroxy-mirtazapine.
Mirtazapine is extensively metabolized by demethylation and hydroxylation followed by glucuronide conjugation. Cytochrome P450 2D6 and cytochrome P450 1A2 are involved in formation of the 8-hydroxy metabolite of mirtazapine, and cytochrome P450 3A4 is responsible for the formation of the N-desmethyl and N-oxide metabolites. Several metabolites possess pharmacological activity, but plasma levels are very low.
Route of Elimination: This drug is known to be substantially excreted by the kidney (75%).
Half Life: 20-40 hours

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Biological Half-Life
20-40 hours

Toxicity Summary
Mirtazapine acts as an antagonist at central pre-synaptic alpha(2)-receptors, inhibiting negative feedback to the presynaptic nerve and causing an increase in NE release. Blockade of heteroreceptors, alpha(2)-receptors contained in serotenergic neurons, enhances the release of 5-HT, increasing the interactions between 5-HT and 5-HT₁ receptors and contributing to the anxiolytic effects of mirtazapine. Mirtazapine also acts as a weak antagonist at 5-HT₁ receptors and as a potent antagonist at 5-HT₂ (particularly subtypes 2A and 2C) and 5-HT₃ receptors. Blockade of these receptors may explain the lower incidence of adverse effects such as anxiety, insomnia, and nausea. Mirtazapine also exhibits significant antagonism at H1-receptors, resulting in sedation. Mirtazapine has no effects on the reuptake of either NE or 5-HT and has only minimal activity at dopaminergic and muscarinic receptors.

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Toxicity Data
LD50: 600-720mg/kg (oral, mice) (L1855)
LD50: 320-490mg/kg (oral, rat) (L1855)

[1]. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. Fall 2001;7(3):249-64.

[2]. Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropharmacology. 1988 Apr;27(4):399-408.

[3]. The Antidepressant Mirtazapine Inhibits Hepatic Innate Immune Networks to Attenuate Immune-Mediated Liver Injury in Mice. Front Immunol. 2019 Apr 12;10:803.

Pharmacodynamics
**General effects and a note on suicidality** Mirtazapine is effective in treating moderate to severe depression and treats many symptoms normally associated with this condition. These symptoms may include disturbed sleep, lack of appetite, and anhedonia, in addition to anxiety.. It is important to note that suicidal ideation and behavior may emerge or increase during treatment with mirtazapine, as with any other antidepressant. This risk is especially pronounced in younger individuals. Patients, medical professionals, and families should monitor for suicidal thoughts, worsening depression, anxiety, agitation, sleep changes, irritable behavior, aggression, impulsivity, restlessness, and other unusual behavior when this drug is taken or the dose is adjusted. Do not administer mirtazapine to children. When deciding to prescribe this drug, carefully consider the increased risk of suicidal thoughts and behavior, especially in young adults. **Effects on appetite and weight gain** In addition to the above effects, mirtazapine exerts stimulating effects on appetite, and has been used for increasing appetite and decreasing nausea in cancer patients. Some studies and case reports have shown that this drug improves eating habits and weight gain in patients suffering from anorexia nervosa when administered in conjunction with psychotherapy and/or other psychotropic drugs. In a clinical trial, women with depression experienced a clinically significant mean increase in body weight, fat mass, and concentrations of leptin when treated with mirtazapine for a 6-week period, with a lack of effect on glucose homeostasis. **Effects on sleep** The use of mirtazapine to treat disordered sleep has been leveraged from its tendency to cause somnolence, which is a frequently experienced adverse effect by patients taking this drug. Mirtazapine has been shown to exert beneficial effects on sleep latency, duration, and quality due to its sedating properties. Insomnia is a common occurrence in patients with depression, and mirtazapine has been found to be efficacious in treating this condition.

C17H19N3

265.35

265.157

C, 76.95; H, 7.22; N, 15.84

85650-52-8

(S)-Mirtazapine; 61337-87-9; (S)-Mirtazapine-d3; (R)-Mirtazapine; 61364-37-2; Mirtazapine-d3; 1216678-68-0; Mirtazapine-d4; 1215898-55-7; (R)-Mirtazapine-d3; 85650-52-8; 61337-67-5 (deleted); 1448014-35-4 (HCl); 207516-99-2 (HCl); 207516-99-2 (2HCl); 868363-97-7 (HBr); 868528-74-9 (HBr); 341512-89-8 (hemihydrate)

4205

White to off-white solid powder

1.2±0.1 g/cm3

432.4±45.0 °C at 760 mmHg

114-116ºC

215.3±28.7 °C

0.0±1.0 mmHg at 25°C

1.668

2.75

0

3

0

20

345

0

N1C2N3C(C4C(CC=2C=CC=1)=CC=CC=4)CN(C)CC3

RONZAEMNMFQXRA-UHFFFAOYSA-N

InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3

5-methyl-2,5,19-triazatetracyclo[13.4.0.02,7.08,13]nonadeca-1(15),8,10,12,16,18-hexaene

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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