D₂ Receptor ( IC50 = 2.8 nM ); D₃ Receptor ( IC50 = 3.2 nM )

Only the highest dose of Amisulpride (100 mg/kg) significantly reduces dopamine levels in the striatum or limbic system. At doses of 20 and 100 mg/kg, amisulpride dramatically increases the synthesis of dopamine in the rat limbic system and striatum. Amisulpride (0.5 to 75 mg/kg) does not cause an additional rise in dopa accumulation in the striatum, but it does cause a slight acceleration of dopamine synthesis in the limbic system at 75 mg/kg. Amisulpride (10 mg/kg) raises extracellular dopamine levels when compared to vehicle-treated controls. The stimulation-evoked release of dopamine increases in a dose- and time-dependent manner when amisulpride (0.5 to 15 mg/kg s.c.) is administered. Amisulpride (70 mg/kg, p.o.) considerably lengthens swimming behavior in both acute studies [F(3,28)=45.90, p<0.01].[2].

Amisulpride's functional effects at the dopamine D₃ receptor subtype are evaluated. In summary, [³H]thymidine incorporation measures the mitogenic response induced in NG108-15 neuroblastoma-glioma cells stably transfected with human dopamine D₃ receptor cDNA by adding 10 nM quinpirole in the presence of 1 μM forskolin. When Amisulpride concentrations increase from 0.1 to 100 nM, the antagonism of quinpirole-induced mitogenesis is measured[1].

Absorption, Distribution and Excretion
Following oral administration, amisulpride is rapidly absorbed with absolute bioavailability of 48%. Amisulpride has two absorption peaks, with one rapidly achieved within one hour post-dose and a second peak occurring between three to four hours post-dose. Following oral administration of a 50 mg dose, two peak plasma concentrations were 39 ± 3 and 54 ± 4 ng/mL. Following intravenous administration, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases by 50% within approximately 15 minutes. The AUC(0-∞) increases dose-proportionally in the dose range from 5 mg to 40 mg, which is about four times the maximum recommended dose. In healthy patients receiving intravenous amisulpride, the mean (SD) Cmax was 200 (139) ng/mL at the dose of 5 mg and 451 (230) ng/mL at the dose of 10 mg. The AUC ranged from 136 to 154 ng x h/mL in the dose range of 5 mg to 10 mg. In patients undergoing surgery, the mean (SD) Cmax ranged from 127 (62) to 161 (58) ng/mL at the dose of 5 mg. At the dose of 10 mg, it was 285 (446) ng/mL. The AUC ranged from 204 to 401 ng x h/mL.
Following intravenous administration, about 74% of amisulpride is excreted in urine, where 58% of the recovered dose was excreted as unchanged amisulpride. About 23% of the dose is excreted in feces, with 20% of the excreted dose as unchanged parent drug. Following intravenous administration, about four metabolites were identified in urine and feces, accounting for less than 7% of the total dose administered. About 22 to 25% of orally administered amisulpride is excreted in urine, mostly as the unchanged parent drug.
Following oral administration, the volume of distribution is 5.8 L/kg. Following intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 L in surgical patients and 171 L in healthy subjects.
The plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects following intravenous administration. Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects.

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Metabolism / Metabolites
Amisulpride undergoes minimal metabolism and its metabolites in plasma are largely undetectable. Two identified metabolites, formed by de-ethylation and oxidation, are pharmacologically inactive and account for approximately 4% of the dose. Metabolites remain largely uncharacterized. Metabolism of amisulpride does not involve cytochrome P450 enzymes.

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Biological Half-Life
Elimination is biphasic. The elimination half-life of amisulpride is approximately 12 hours after an oral dose. The mean elimination half-life is approximately four to five hours in both healthy subjects and patients undergoing surgery receiving intravenous amisulpride.

Hepatotoxicity
Intravenous single doses of amisulpride are generally well tolerated, and in multiple randomized controlled trials were not associated with rates of serum aminotransferase or bilirubin elevations above those that occurred in placebo treated subjects. While oral amisulpride has been linked to transient serum aminotransferase elevations during therapy, single intravenous doses of amisulpride have not been linked to liver enzyme elevations in excess of rates found postoperatively. Since its approval and more widespread use, amisulpride has not been implicated in cases of clinically apparent liver injury.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
Plasma protein binding ranges from 25% to 30% in the concentration range from 37 to 1850 ng/mL. Amisulpride distributes into erythrocytes.

[1]. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther. 1997 Jan;280(1):83-97.

[2]. Evaluation of antidepressant like property of amisulpride per se and its comparison with fluoxetine and olanzapine using forced swimming test in albino mice. Acta Pol Pharm. 2009 May-Jun;66(3):327-31.

Pharmacodynamics
Amisulpride is a selective dopamine D2 and D3 receptor antagonist with no affinity towards other dopamine receptor subtypes. Amisulpride is an atypical antipsychotic agent that works as an antagonist at dopamine receptors in the limbic system. Since it works preferentially in the limbic system, amisulpride is less likely to be associated with extrapyramidal adverse effects than other atypical antipsychotic agents. Amisulpride has no affinity for serotonin, alpha-adrenergic, H1-histamine, cholinergic, and sigma receptors. In clinical trials, amisulpride improved reduced secondary negative symptoms, affective symptoms, and psychomotor retardation in patients with acute exacerbation of schizophrenia. Notably, amisulpride has a differential target binding profile at different doses: at low doses, amisulpride selectively binds to presynaptic dopamine autoreceptors. At high doses, it preferentially binds to post-synaptic dopamine receptors. This explains how amisulpride reduces negative symptoms at low doses and mediates antipsychotic effects at high doses. One study alluded that the antinociceptive effects of amisulpride are mediated through opioid receptor acvitation and D2 receptor antagonism. The actions of amisulpride at opioid receptors may explain its pro-convulsant properties. Amisulpride is also an antiemetic agent that prevents and alleviates postoperative nausea and vomiting. It primarily works by blocking dopamine signalling in the chemoreceptor trigger zone, which is a brain area that relays stimuli to the vomiting center. In clinical trials comprising Caucasian and Japanese subjects, amisulpride caused dose- and concentration-dependent prolongation of the QT interval; thus, intravenous infusion under a strict dosing regimen and close monitoring of patients with pre-existing cardiovascular conditions are recommended. Amisulpride increases plasma prolactin levels, leading to an association with benign pituitary tumours such as prolactinoma.

C17H27N3O4S

369.48

369.172

C, 55.26; H, 7.37; N, 11.37; O, 17.32; S, 8.68

71675-85-9

Amisulpride-d5; 1216626-17-3; Amisulpride hydrochloride; 81342-13-4; Amisulpride-d5 N-Oxide; 1794756-15-2

2159

Solid powder

1.2±0.1 g/cm3

558.9±50.0 °C at 760 mmHg

124-128ºC

291.8±30.1 °C

0.0±1.5 mmHg at 25°C

1.546

1.6

2

6

7

25

549

0

CCN1C(CNC(C2=CC(S(=O)(CC)=O)=C(N)C=C2OC)=O)CCC1

NTJOBXMMWNYJFB-UHFFFAOYSA-N

InChI=1S/C17H27N3O4S/c1-4-20-8-6-7-12(20)11-19-17(21)13-9-16(25(22,23)5-2)14(18)10-15(13)24-3/h9-10,12H,4-8,11,18H2,1-3H3,(H,19,21)

4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxybenzamide

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 (6.77 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 (6.77 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 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 3: 2.5 mg/mL (6.77 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
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.)