Zotepine exhibits multiple antagonistic profiles and strong affinities to α1-adrenergic, α₂-adrenergic, Dopamine D₂, Histamine H1, Muscarinic, 5-HT_1A, 5-HT_1D, 5-HT_2A, and 5-HT_2C receptors, with K_ds of 7.3, 180, 8, 3.3, 330, 280, 80, 2.6, 3.2 nM, respectively[1].

Zotepine (1-3 mg/kg; a single i.p.) dose-dependently raises noradrenaline, dopamine, glutamate release, and GABA levels without changing 5-HT levels in the medial prefrontal cortex of rats[2].

Male Sprague-Dawley rats (250-300 g)
1, 3 mg/kg
A single i.p.

Absorption, Distribution and Excretion
Preclinical pharmacokinetic studies have shown a dose-dependent increase in plasma levels with a tmax between 2-4 hours and Cmax from 6.9-19.6 ng/ml when administered in a dose of 25-100 mg of zotepine. The maximum concentration peaks and slow declines thereafter. When administered orally in preclinical studies, zotepine was proven to be absorbed rapidly and almost completely from the gastrointestinal tract.The unchanged drug and metabolites are rapidly distributed to the tissues.
Only small amounts of the unchanged zotepine are excreted in the urine and fecal excretion through the bile is the main route of elimination of both the unchanged drug and its metabolites.
The apparent volume of distribution of zotepine is 109 L/kg.
The apparent oral clearance of zotepine is 4.6 mg/h.kg.

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Metabolism / Metabolites
Zotepine is well metabolized in the body, it actually undergoes extensive first-pass metabolism to the metabolite norzotepine and several inactive metabolites. The main enzymes involved in zotepine metabolism are CYP1A2 and CYP3A4. Some of the main metabolic pathways include N-demethylation and oxygenation of N or S atoms, hydroxylation of the aromatic ring and consecutive conjugation.
Zotepine has known human metabolites that include 3-hydroxy-zotepine, Zotepine N-oxide, Zotepine -oxide, Norzotepine, and 2-hydroxy-zotepine.

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Biological Half-Life
The half-life of zotepine is reported to be of 21 hours.

Protein Binding
Plasma protein binding of zotepine and its major active metabolite norzotepine account for 97% of the administered dose.

[1]. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci. 2000 Nov 24;68(1):29-39.

[2]. Effects of zotepine on extracellular levels of monoamine, GABA and glutamate in rat prefrontal cortex. Br J Pharmacol. 2009 Jun;157(4):656-65.

Zotepine is a dibenzothiepine and a tertiary amino compound. It has a role as an alpha-adrenergic drug, a serotonergic drug and a second generation antipsychotic.
Zotepine, with the formula (2-chloro-11-(2-dimethyl-amino-ethoxy)-dibenzo thiepin, is a neuroleptic drug. It was designed and synthesized by Fujisawa Pharmaceutical Co Ltd. It has been used as an antipsychotic in Japan, India and some places in Europe like UK and Germany since 1980's. Zotepine was never approved by the FDA. In 1993, it was classified as inactive drug substance (Status I, Type II) and in 1995 the FDA studied the manufacturing procedures of Zotepine tablets in Germany, but the status remained inactive. When the analysis of antipsychotics was retaken in 2016 by the FDA, zotepine did not reach the threshold effect to be further studied.. In the EMA, by 2015 it was under pharmacovigilance studies for the potential treatment of acute renal failure.

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Drug Indication
Zotepine, like other atypical antipsychotics, is considered as the first-line treatment in newly diagnosed schizophrenia. It is usually thought to be an option of choice for managing acute schizophrenic episodes when discussion with the patient is not possible. Zotepine, as an atypical antipsychotic, is used in patients who are suffering unacceptable side effects from conventional antipsychotics or in relapse patients that were inadequately controlled. It is important to consider that the indications stated above are related to atypical antipsychotics, that zotepine is not currently FDA, Canada or EMA approved and that studies have not shown any additional benefit when compared with other approved atypical antipsychotics. Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels and behaves. It is usually marked for a loose reality perspective delineated by hallucinations, delusions and thought and movement disorders.

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Mechanism of Action
Zotepine is a dopamine antagonist that has a high affinity for D1- and D2-like receptors. It presents a strong antagonism for several serotonin receptors, such as 5-HT2a, 5-HT2c, 5-HT6 and 5-HT7. Zotepine activities are also related to the inhibition of noradrenaline reuptake and serotonergic activity. All these effects allow zotepine to improve the negative and cognitive symptoms of schizophrenia.

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Pharmacodynamics
In preclinical studies, zotepine is characterized by the presence of a strong antiserotonergic activity when compared with other neuroleptic drugs. It has also been reported to present elevations in the seizure threshold in the amygdaloid nucleus. When zotepine's effects were analyzed by electroencephalography, it was noted a typical response of a low-potency neuroleptics of the sedative type. Administration of zotepine has shown improvements in numerical movements and complex reaction. These effects tend to be accompanied by increases in pulse rate, increase in prolactin levels and some typical neuroleptic side effects.

C18H18CLNOS

331.86

331.079

C, 65.15; H, 5.47; Cl, 10.68; N, 4.22; O, 4.82; S, 9.66

26615-21-4

5736

White to off-white solid powder

1.3±0.1 g/cm3

478.4±45.0 °C at 760 mmHg

90-91 °C

243.2±28.7 °C

0.0±1.2 mmHg at 25°C

1.656

6.57

0

3

4

22

401

0

CN(C)CCOC1=CC2=CC=CC=C2SC3=C1C=C(C=C3)Cl

HDOZVRUNCMBHFH-UHFFFAOYSA-N

InChI=1S/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3

2-(3-chlorobenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethylethanamine

Zotepine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: ~25 mg/mL (~75.3 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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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 (Please use freshly prepared in vivo formulations for optimal results.)