5-HT1A Receptor; 5-HT2A Receptor; 5-HT2B Receptor; 5-HT2C Receptor; D2 Receptor; D3 Receptor; D4 Receptor

阿立哌唑月桂醇是由十二烷酸的羧基与7-{4-[4-（2,3-二氯苯基）哌嗪-1-基]丁氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]甲醇的羟基缩合而成的十二烷酸酯。它是阿立哌唑的前药，用于治疗精神分裂症。它具有h1受体拮抗剂、第二代抗精神病药、血清素激动剂和前药的作用。它是十二烷酸酯、喹诺酮、二氯苯、n -芳基哌嗪、n -烷基哌嗪、芳香醚和-内酰胺。[1]

中间体 N-对应的阿立哌唑参与月桂酰阿立哌唑（车载产品；1.87 mg/mL）的体内生物转化。因此，根据外围数据，月桂酰阿立哌唑具有高生物转化率，导致观察到的N-对应甲基阿立哌唑的合成。当动物服用月桂酰亚立曲唑时，亚立曲唑的浓度非常高[1]。

缓冲液中体外转化[2]
为了使n -羟甲基阿立哌唑/aripiprazole lauroxil自发转化为阿立哌唑，制备了DMSO-d6的原液，将原液加入pH为7.4的磷酸盐缓冲液中，即含有0.5% v/v DMSO-d6，即可开始反应。缓冲液中n -羟甲基阿立哌唑/aripiprazole lauroxil的最终浓度为9µM，等于阿立哌唑在水中的溶解度。在25°C和37°C的连续测量中，[2]
1H NMR波谱在600.163 MHz下在配备5 mm TCI CryoProbe的Bruker AV-III-600上测量。参照DMSO-d6 （2.51 ppm）。溶剂抑制与激发雕刻使用方形180脉冲的4毫秒应用于水溶液。采集时间为1.7 s，重复延迟为3 s，傅里叶变换前进行1.0 Hz的洛伦兹线展宽，积分前对芳香区进行4次多项式拟合的基线校正。

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血浆中体外转化[2]
体外实验采用三次重复，将30µL 1µM aripiprazole lauroxil溶解于乙醇中，加入雌性Sprague Dawley大鼠1.47 mL血浆中，37℃。加峰血浆在37℃下保存，在加峰后0.5和1.0 h取50µL。等分液立即用含有0.4%柠檬酸的200µL冷乙腈处理，保存在-80°C，直到按照第2.7节的描述进行分析。

Animal/Disease Models: Female SD (SD (Sprague-Dawley)) rats[1]
Doses: 1.87 mg/ml
Route of Administration: Blood samples were collected at 5, 15, 30 minutes and 1, 2, 4, 6, 8 and 24 hrs (hrs (hours)) after administration.
Experimental Results: Displayed clearance: 0.32 ± 0.11 L/h/kg.

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Formulations for the in vivo study [2]
An emulsion for intravenous administration containing each of the three compounds (i.e., aripiprazole, N-hydroxymethyl-aripiprazole or aripiprazole lauroxil) in equimolar concentrations equivalent to 1 mg aripiprazole was produced. The emulsions consisted of compound, 20% w/w fractionated coconut oil, 1.2% w/w lecithin, 2% w/w glycerol and q.s. water. The amount of each compound added was 1 mg aripiprazole/mL, 1.2 mg N-hydroxymethyl-aripiprazole/mL or 1.87 mg aripiprazole lauroxil/mL, i.e., equimolar. Each of the three compounds was dissolved in the oil together with lecithin and gently heated to 50 °C with continuous stirring. Glycerol was added to the aqueous phase as an isotonic agent and the aqueous phase was heated to 50 °C. The two phases were mixed and homogenised to a pre-emulsion by rapid stirring for 1 min. The pre-emulsion was placed on ice and the droplet size was further reduced by means of a homogeniser equipped with a standard microtip at a power output of 5 (Sonifier Cell Disruptor, Model B15, Branson, Pusan, Korea) for 10 min. The formulation was then filtered through a 0.45 µm sterile filter into a sterilised glass bottle with a rubber membrane and a crimped lid.

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In vivo study[2]
The protocol used for the in vivo study in rats was approved by the institutional animal ethics committee in accordance with Danish law regulating experiments on animals and in compliance with EC directive 2010/63/EU, and the NIH guidelines on animal welfare. Female Sprague Dawley rats, weighing 248–276 g on the day of administration, were used for the pharmacokinetic studies (n = 6 per group). The animals were acclimatised for a minimum of 5 days in groups of 2 on wooden bedding in plastic cages, 595 × 380 × 200 mm3, with a stainless steel lid in humidity- and temperature-controlled ventilation cupboards, relative humidity 40–60%, temperature 20 ± 1 °C, light from 6:00–18:00 h. The animals had free access to a standard rodent diet and water ad libitum during the study.[2]
The animals were randomly assigned to three groups (n = 6 per group) receiving either aripiprazole, N-hydroxymethyl-aripiprazole or aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg. The animals were dosed by injection into the tail vein with a submicron emulsion containing a molar concentration equivalent to 1 mg aripiprazole/mL. Blood samples of 100 µL were obtained from the lateral tail vein by individual vein puncture and collected into potassium–EDTA tubes. Samples was taken at 5, 15, 30 min and 1, 2, 4, 6, 8 and 24 h after administration. Plasma was harvested immediately by 10 min of centrifugation at 4 °C, 2765g and stored at -80 °C until analysed. At the end of the experiment, the animals were sacrificed.

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Absorption, Distribution and Excretion
Following a single intramuscular injection of sustained-release aripiprazole, aripiprazole is detectable in systemic circulation within 5 to 6 days and continues to be released for 36 days. Aripiprazole concentrations increase with repeated administration of aripiprazole and reach steady state after the fourth monthly injection. Systemic exposure is similar after intramuscular injection of aripiprazole into the deltoid and gluteal muscles. According to pharmacokinetic studies of aripiprazole, less than 1% of the unchanged aripiprazole is excreted in the urine, and approximately 18% of the oral dose is excreted unchanged in the feces. Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole after intramuscular injection is 268 L, indicating extensive extravascular distribution after absorption. Studies in healthy volunteers have shown that aripiprazole can cross the blood-brain barrier. In rats, the clearance of aripiprazole was 0.32 ± 0.11 L/h/kg after injection of aripiprazole equivalent to 5 mg/kg aripiprazole. Metabolites/Metabolites Aripiprazole is hydrolyzed by esterases to N-hydroxymethylaripiprazole. N-hydroxymethylaripiprazole undergoes rapid non-enzymatic spontaneous cleavage or water-mediated hydrolysis to produce aripiprazole, which is the main source of the pharmacological action of aripiprazole. Aripiprazole is further metabolized in the liver by CYP3A4 and CYP2D6 to dehydroaripiprazole, which retains some pharmacological activity. Dehydroaripiprazole has a similar affinity for the D2 receptor to aripiprazole and accounts for 30-40% of aripiprazole exposure in plasma. Genetic polymorphism in cytochrome P450 2D6 leads to pharmacokinetic differences between CYP2D6 metabolic phenotypes, thus requiring appropriate dose adjustments.

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Biological Half-Life
After injection of aripiprazole loloxi 441, 662 and 882 mg every 4 weeks, the mean terminal elimination half-life of aripiprazole ranged from 29.2 days to 34.9 days.

Protein Binding

Aripiprazole and its main metabolites have a serum protein binding rate of >99% at therapeutic concentrations, primarily binding to albumin.

[1]. Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents.CNS Drugs. 2018 Mar;32(3):241-257.

[2]. Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug.Results Pharma Sci. 2014 May 2;4:19-25.

Aripiprazole lorazepam is a dodecanoate ester, formed by the condensation of the carboxyl group of dodecanoic acid with the hydroxyl group of 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-2-oxo-3,4-dihydroquinoline-1(2H)-yl]methanol. It is a prodrug of aripiprazole used to treat schizophrenia. It has multiple functions, including H1 receptor antagonist, second-generation antipsychotic, serotonergic agonist, and prodrug action. It is a dodecanoate ester, quinolone, dichlorobenzene, N-arylpiperazine, N-alkylpiperazine, aromatic ether, and δ-lactam compound. Aripiprazole lorazepam is a long-acting injectable atypical antipsychotic used to treat schizophrenia in adults. It is a prodrug of aripiprazole, which acts as a partial agonist of D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors. Schizophrenia affects approximately 1% of the adult population in the United States and about 26 million people worldwide. It is a chronic neurological disorder that can lead to cognitive and executive dysfunction. Due to adverse health consequences, patients experience significantly reduced quality of life and often face social stigma and discrimination. Schizophrenia is characterized by positive symptoms (such as delusions, hallucinations, thought disorders, and catatonia) and negative symptoms (including social withdrawal, anhedonia, and emotional blunting). D2 receptors are the most commonly used target for antipsychotic drugs treating schizophrenia: positive symptoms are thought to be caused by overactive dopaminergic pathways in the mesolimbic system activating D2 receptors, while negative symptoms may be caused by reduced activity in the mesocortical dopaminergic pathways (primarily D1 receptors). In a randomized, double-blind clinical trial, aripiprazole and lorazepam were used to treat adult patients with schizophrenia, resulting in improvements in both positive and negative symptom scores by day 85 of treatment. Aripiprazole and lorazepam was initially approved by the U.S. Food and Drug Administration (FDA) in October 2015 under the brand name Aristada for the treatment of schizophrenia. This drug is administered via intramuscular injection. For treatment-naïve patients, tolerability should be assessed before administration. On July 2nd, the FDA approved another aripiprazole lorazepam formulation, marketed as Aristada Initio, which can be used to immediately initiate Aristada treatment at any dose. Patients can take Aristada Initio concurrently with a single oral 30 mg dose of aripiprazole to achieve appropriate aripiprazole plasma concentrations more quickly. Long-acting injectable aripiprazole lorazepam has similar efficacy and safety to aripiprazole, but with a reduced dosing frequency, improving patient adherence.
See also: Aripiprazole (containing the active ingredient).
Drug Indications

Aripiprazole lorazepam is indicated for the treatment of schizophrenia and related psychotic disorders.
FDA Label
Mechanism of Action

The pharmacological activity of aripiprazole lorazepam is primarily mediated by its metabolite aripiprazole, followed by dehydroaripiprazole. Aripiprazole acts as a partial agonist of dopamine D2 receptors and serotonin 5-HT1A receptors, and an antagonist of serotonin 5-HT2A receptors. The expected outcome of antipsychotic drug treatment for schizophrenia is the inhibition of dopaminergic transmission in the limbic system and the enhancement of dopaminergic transmission in the prefrontal cortex. Aripiprazole, as a partial agonist of D2 receptors in the mesolimbic dopamine pathway, acts as a functional antagonist in the mesolimbic dopamine pathway, reducing the activity of the dopaminergic pathway. This leads to a reduction in positive symptoms and extrapyramidal motor side effects of schizophrenia. Conversely, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is associated with negative symptoms and cognitive impairment. The antagonistic effect of aripiprazole on 5-HT2A receptors may alleviate negative symptoms and cognitive impairment in schizophrenia. 5-HT2A receptors are Gi/Go-coupled receptors that, upon activation, inhibit neuronal activity by reducing neuronal excitability and decreasing neurotransmitter release at nerve endings. In the substantia nigra-striatal pathway, 5-HT2A receptors regulate dopamine release. Aripiprazole, by antagonizing 5-HT2A receptors, relieves the inhibition of dopamine release in the striatum and increases neurotransmitter levels at nerve endings. The combined effect of D2 receptor and 5-HT2A receptor antagonism is thought to counteract the increased extrapyramidal side effects caused by enhanced dopamine function. Blocking 5-HT2A receptors may also lead to the regulation of glutamate release in the midbrain cortex circuit; glutamate is a neurotransmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist of these receptors, reducing 5-HT release. This leads to enhanced dopamine release in the striatum and prefrontal cortex. Therapeutic doses of aripiprazole have been reported to occupy up to 90% of the brain's D2 receptors in a dose-dependent manner. Aripiprazole targets different receptors, leading to drug-related adverse reactions; for example, its antagonism of α1-adrenergic receptors can cause orthostatic hypotension. Antagonism of histamine H1 receptors may explain the drowsiness observed after taking the drug. Schizophrenia is a chronic illness that patients experience remission and relapse throughout their lives. Antipsychotic medications are the primary means of treating this illness. Long-acting injectable (LAI) antipsychotics are an ideal alternative to oral formulations because they can improve patient adherence. Many second-generation antipsychotics (SGAs) are available in long-acting injectable formulations. These include paliperidone, aripiprazole, olanzapine, and risperidone. This article reviews the most recently developed and approved formulations of these drugs—aripiperazole monohydrate, aripiprazole-loprolate, and paliperidone palmitate. While these drugs were initially formulated as once-monthly doses, a three-monthly injectable formulation of paliperidone palmitate has been approved, marking the first long-acting injectable to extend the dosing interval beyond the usual monthly dose. In addition, aripiprazole lorazepam formulations every six and eight weeks have been developed. All long-acting injectable formulations of second-generation antipsychotics have shown superior efficacy compared to placebo and comparable safety and tolerability to their corresponding oral formulations (if injection site reactions are ignored). Long-acting injectable formulations of first-generation antipsychotics (e.g., haloperidol decanoate) have recently been compared with long-acting injectable formulations of second-generation antipsychotics, with comparable efficacy and both showing the expected adverse reactions of their respective drugs. Despite the availability of long-acting injectables (LAIs), their use remains challenging. Educating patients and clinicians about the use of long-acting injectables and continuing to develop these drugs are important steps to ensure that patients most likely to benefit from them have access to them. [1]

659.326

C, 65.44; H, 7.78; Cl, 10.73; N, 6.36; O, 9.69

1259305-29-7

129722-12-9;851220-85-4 (hydrate);1259305-26-4 (cavoxil);1259305-29-7 (lauroxil);

49831411

White to off-white solid powder

81-83

8.743

62.32

0

6

20

45

858

0

CCCCCCCCCCCC(=O)OCN1C2=C(C=CC(=C2)OCCCCN3CCN(CC3)C4=CC=CC(=C4Cl)Cl)CCC1=O

DDINXHAORAAYAD-UHFFFAOYSA-N

InChI=1S/C36H51Cl2N3O4/c1-2-3-4-5-6-7-8-9-10-16-35(43)45-28-41-33-27-30(19-17-29(33)18-20-34(41)42)44-26-12-11-21-39-22-24-40(25-23-39)32-15-13-14-31(37)36(32)38/h13-15,17,19,27H,2-12,16,18,20-26,28H2,1H3

[7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-2-oxo-3,4-dihydroquinolin-1-yl]methyl dodecanoate

Aripiprazole lauroxil; 1259305-29-7; Aristada; RDC-3317; ALKS 9072; Aristada initio; ALKS 9070; RDC 3317;

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)

DMSO : ~8.33 mg/mL (~12.61 mM)

配方 1 中的溶解度: ≥ 0.83 mg/mL (1.26 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 8.3 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。