5-HT_1A Receptor ( Ki = 4.2 nM ); 5-HT_2A Receptor; 5-HT_2B Receptor; 5-HT_2C Receptor; D₂ Receptor; D₃ Receptor; D₄ Receptor
Aripiprazole (OPC-14597) is a partial agonist of dopamine D₂ receptors (rat striatal membranes, Ki = 0.34 nM) and dopamine D₃ receptors (human recombinant, Ki = 0.4 nM); it acts as a full agonist of 5-hydroxytryptamine 1A (5-HT₁A) receptors (human recombinant, Ki = 1.7 nM) and an antagonist of 5-HT₂A receptors (human cortical membranes, Ki = 3.4 nM) [1,2]
- Aripiprazole (OPC-14597) has negligible affinity for dopamine D₁ receptors (Ki > 1000 nM) and muscarinic M₁ receptors (Ki > 5000 nM) in human brain membranes [3]
- Aripiprazole (OPC-14597) weakly inhibits human cytochrome P450 enzyme CYP2D6 (IC₅₀ = 6.8 μM) and shows no significant inhibition of CYP3A4 (IC₅₀ > 50 μM) [4]

阿立哌唑以高亲和力与 G 蛋白偶联和非偶联状态的受体结合。阿立哌唑可有效激活 D2 受体介导的 cAMP 积累抑制作用。阿立哌唑对 h5-HT(2B)-、hD(2L)- 和 hD(3)- 多巴胺受体具有最高的亲和力，但对其他几种 5-HT 受体 (5-HT) 也具有显着的亲和力 (5-30 nM) (1A)、5-HT(2A)、5-HT(7))，以及 α(1A)-肾上腺素能受体和 hH(1)-组胺受体。阿立哌唑对其他 G 蛋白偶联受体的亲和力较低 (30-200 nM)，包括 5-HT(1D)、5-HT(2C)、α(1B)-、α(2A)-、α(2B) -、α(2C)-、β(1)-、β(2)-肾上腺素能受体和 H(3)-组胺受体。阿立哌唑是 5-HT(2B) 受体的反向激动剂，并对 5-HT(2A)、5-HT(2C)、D(3) 和 D(4) 受体显示部分激动作用。

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多巴胺D₂受体部分激动作用：在表达人D₂受体的HEK 293细胞中，Aripiprazole (OPC-14597)（10⁻¹⁰-10⁻⁶ M）可浓度依赖性刺激cAMP生成（部分激动）：cAMP最大积累量为完全激动剂喹吡罗的45%，EC₅₀=12 nM；其拮抗喹吡罗诱导的cAMP生成，IC₅₀=0.56 nM[3]
- 5-HT₁A受体激动作用：在表达人5-HT₁A受体的CHO细胞中，Aripiprazole (OPC-14597)（10⁻⁹-10⁻⁶ M）可剂量依赖性抑制毛喉素诱导的cAMP生成（完全激动）：10⁻⁷ M使cAMP减少70%，EC₅₀=2.1 nM[2]
- 5-HT₂A受体拮抗作用：在大鼠皮层切片中，Aripiprazole (OPC-14597)（10⁻⁸-10⁻⁶ M）可浓度依赖性阻断5-HT诱导的磷脂酶C激活（5-HT₂A信号标志物）：10⁻⁷ M使激活率降低65%，IC₅₀=4.2 nM[1]
- CYP2D6抑制作用：在人肝微粒体中，Aripiprazole (OPC-14597)（1-100 μM）抑制CYP2D6介导的右美沙芬O-去甲基化反应：10 μM使代谢产物生成减少50%（IC₅₀=6.8 μM），对CYP1A2或CYP2C9活性无影响[4]

阿立哌唑可降低未接受药物治疗的大鼠内侧前额叶皮层和纹状体中细胞外 5-HIAA 的浓度，但不会降低慢性阿立哌唑预处理大鼠的浓度。阿立哌唑，0.1 mg/kg 和 0.3 mg/kg，显着增加大鼠海马的多巴胺释放。阿立哌唑，0.3 mg/kg，轻微但显着地增加内侧前额皮质中的多巴胺释放，但不增加伏核中的多巴胺释放。阿立哌唑，3.0 mg/kg 和 10 mg/kg，显着减少伏隔核中的多巴胺释放，但不影响医学前额皮质。阿立哌唑，0.3 mg/kg，可短暂增强氟哌啶醇（0.1 mg/kg）诱导的内侧前额叶皮质中的多巴胺释放，但抑制伏隔核中的多巴胺释放。

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大鼠阿朴吗啡诱导刻板行为模型：在雄性Sprague-Dawley大鼠中，于阿朴吗啡（5 mg/kg，腹腔注射）给药前30 min口服Aripiprazole (OPC-14597)（1、3、10 mg/kg），可剂量依赖性减少刻板行为（嗅探、舔舐）：3 mg/kg剂量较溶媒组使总刻板行为时间减少65%，且不影响自发活动（旷场实验）[1]
- 小鼠强迫游泳实验（FST）：在雄性ICR小鼠中，口服Aripiprazole (OPC-14597)（3、10、30 mg/kg）60 min后进行FST，可减少不动时间：10 mg/kg剂量较溶媒组使不动时间减少50%，提示抗抑郁样作用[2]
- 大鼠嗅球切除（OBX）模型：在OBX抑郁模型大鼠中，每日口服Aripiprazole (OPC-14597)（5 mg/kg）持续14天，可逆转OBX诱导的过度活动（旷场移动距离减少40%），并使蔗糖偏好恢复正常（从42%升至73%）[4]
- 犬精神分裂症样模型：在苯环利定（PCP）诱导过度活动的雄性比格犬中，于PCP给药前15 min皮下注射Aripiprazole (OPC-14597)（0.1、0.3 mg/kg），0.3 mg/kg剂量在2 h内使过度活动减少70%[3]

放射性配体结合试验[2]
大量瞬时和稳定转染的克隆人类cdna，通过国家精神卫生研究所精神活性药物筛选计划（NIMH-PDSP）的资源获得，用于放射配体结合和功能分析，如前面所述(Rothman等人，2000；Tsai et al ., 2000)。表1列出了放射配体结合测定的条件，以及标准化合物的KD值。在初始筛选试验中，以10 μM的浓度对大量gpcr、离子通道和转运体进行了阿立哌唑四次重复的测试。对于>50%抑制的分子靶点，使用至少6个浓度<强>阿立哌唑的浓度来测定Ki；使用GraphPad Prism计算四份Ki值。[125I]DOI竞争试验按照前面的描述进行（Choudhary等，1992），并做了以下改变：将12个阿立哌唑的稀释度，范围为0.01-3000 nM，与[125I]DOI （0.3 nM）在25°C下，以总体积为0.25 ml，结合缓冲液（50 mM Tris缓冲液，pH 7.4, 0.5 mM EDTA, 10 mM MgCl2）中5-20 μg的膜蛋白孵育1小时。用Brandel细胞收割机在聚乙烯亚胺预处理（0.3%）Whatman GF/C过滤器上进行三次冷水洗涤，收获膜。结合滤光片的放射性是用液体闪烁计数来量化的。

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阿立哌唑是第一个下一代非典型抗精神病药，其作用机制不同于目前上市的典型和非典型抗精神病药。阿立哌唑分别在多巴胺能低活性和多活性动物模型中表现出激动剂和拮抗剂的特性。本研究检测了阿立哌唑与单一人群D2受体的相互作用，以进一步阐明其药理学特性。在表达重组D2L受体的中国仓鼠卵巢细胞制备的膜中，阿立哌唑对G蛋白偶联和非偶联状态的受体都具有高亲和力。阿立哌唑有效激活D2受体介导的cAMP积累抑制。用烷基化剂n -乙氧羰基-2-乙氧基-1,2-二氢喹啉（EEDQ）灭活部分受体显著降低了阿立哌唑抑制cAMP积累的最大效果。这种效应是在EEDQ浓度不改变多巴胺最大抑制作用的情况下观察到的。与部分激动剂的预期作用一致，增加阿立哌唑浓度阻断多巴胺的作用，其最大阻断作用相当于单独使用阿立哌唑的激动剂作用。阿立哌唑相对于多巴胺的疗效在缺乏多巴胺备用受体的细胞中为25%，在具有受体储备的细胞中为90%。这些结果，连同先前的研究表明部分激动剂对5-羟色胺（5-HT）1A受体的活性和拮抗剂对5-HT2A受体的活性，支持阿立哌唑作为多巴胺- 5-羟色胺系统稳定剂的鉴定。受体活性谱可能是阿立哌唑在动物体内的独特活性及其在人类中的抗精神病活性的基础。［2］

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大鼠纹状体D₂受体结合实验：将大鼠纹状体在冰浴的Tris-HCl缓冲液（50 mM，pH7.4，含120 mM NaCl、5 mM KCl）中匀浆，48,000 × g离心15 min。取50 μg膜蛋白与[³H]-螺哌隆（0.5 nM）及不同浓度的Aripiprazole (OPC-14597)（10⁻¹²-10⁻⁶ M）在25°C孵育60 min。非特异性结合用10 μM氟哌啶醇定义。反应通过预浸泡于0.1%聚乙烯亚胺的GF/B滤膜过滤终止，洗涤3次后，液体闪烁光谱法计数放射性，利用Cheng-Prusoff方程计算Ki值[1]
- 人5-HT₁A受体结合实验（CHO细胞）：将表达人5-HT₁A受体的CHO细胞在HEPES缓冲液（25 mM，pH7.4，含10 mM MgCl₂）中匀浆，50,000 × g离心15 min。取75 μg膜蛋白与[³H]-8-OH-DPAT（0.3 nM）及Aripiprazole（10⁻¹¹-10⁻⁶ M）在25°C孵育90 min。非特异性结合用10 μM甲硫替平确定，过滤和计数步骤同上[2]
- CYP2D6抑制实验（人肝微粒体）：将人肝微粒体（0.5 mg蛋白/mL）在含NADPH（1 mM）、右美沙芬（10 μM，CYP2D6底物）和Aripiprazole (OPC-14597)（1-100 μM）的Tris-HCl缓冲液（50 mM，pH7.4）中37°C孵育30 min。加入冰浴乙腈终止反应，10,000 × g离心10 min后，上清液经HPLC检测右啡烷（代谢产物）生成量，通过浓度-效应曲线推导IC₅₀[4]

阿立哌唑对cAMP生成的影响[2]
福斯克林刺激cAMP生成的抑制作用[2]
如先前报道的那样，在稳定的D4和5- ht1a受体表达细胞系中测量了福斯克林刺激的3 ‘,5 ’环腺苷单磷酸（cAMP）产生的抑制作用(Lawler等，1999；Zhang et al ., 1994)。简单地说，在24孔板中培养细胞，在实验之前用含有100 μM IBMX和100 μM forskolin（全部在冰上）的新鲜F12培养基替换生长培养基。在细胞中加入10倍稀释的阿立哌唑 0.1 ~ 10.000 nM，然后在37℃和5% CO2下孵育20 min。通过抽吸和加入0.5 ml的3%三氯乙酸来终止反应。4℃冷冻1 h， 1000 g旋转15 min。cAMP采用竞争性结合测定法进行了少量修改（Nordstedt和Fredholm， 1990）。测定cAMP含量时，将三氯乙酸提取物（40 μl）加入到含有cAMP测定缓冲液（100 mM Tris-HCl, pH 7.4, 100 mM NaCl, 5 mM EDTA）的反应管中。[3H]每管加入终浓度为1 nM的cAMP，然后加入cAMP结合蛋白（500 μl cAMP缓冲液中约100 μg牛肾上腺皮质粗提物）。反应管在冰上孵育2小时，然后用Brandel细胞收集机收获到浸泡在水中的Whatman GF/C过滤器上。滤光片干燥，结合放射性通过液体闪烁计数来量化。每个样品中cAMP的浓度从0.1至100 pmol /assay的标准曲线估计。

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刺激cAMP产量[2]
使用先前描述的方法在稳定的转染物中研究了5-HT6和5-HT7受体中血清素和阿立哌唑的作用(Max等人，1995；Monsma et al ., 1993；Shen et al ., 1993)。

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HEK 293细胞D₂受体功能实验：将稳定表达人D₂受体的HEK 293细胞以1×10⁴个细胞/孔接种于96孔板，用含10% FBS的DMEM培养24 h。更换为含Aripiprazole (OPC-14597)（10⁻¹⁰-10⁻⁶ M）±喹吡罗（10⁻⁷ M，完全激动剂）的无血清DMEM。30 min后加入毛喉素（10 μM）刺激cAMP生成，通过ELISA试剂盒（450 nm吸光度）检测cAMP水平[3]
- PC12细胞神经元活力实验：将PC12细胞以5×10⁴个细胞/孔接种于24孔板，用含10%马血清的RPMI 1640培养24 h。更换为含Aripiprazole (OPC-14597)（1、5、10 μM）和H₂O₂（200 μM，氧化应激诱导剂）的无血清RPMI。24 h后，MTT法（570 nm吸光度）检测细胞活力：10 μM Aripiprazole 较单独H₂O₂组使活力增加35%[4]

Absorption, Distribution and Excretion
Tablets: Aripiprazole tablets are well absorbed after administration, with peak plasma concentrations reached within 3 to 5 hours; the absolute oral bioavailability of the tablets is 87%. ABILIFY can be taken with or without food. Taking 15 mg ABILIFY tablets with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite dehydroaripiprazole, but delayed the Tmax of aripiprazole by 3 hours and the Tmax of dehydroaripiprazole by 12 hours. Oral Solution: Aripiprazole solution is well absorbed orally. At the same dose, the plasma concentrations of aripiprazole solution are higher than those of the tablets. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole oral solution and 30 mg aripiprazole tablets in healthy subjects, the geometric mean Cmax and AUC values of the solution and tablets were 122% and 114%, respectively. Aripiprazole single-dose pharmacokinetics are linear and dose-proportional in the dose range of 5 mg to 30 mg. Sustained-release injectable suspension, administered every two months: Due to the low solubility of aripiprazole particles, the time to systemic circulation is prolonged after intramuscular injection in the buttock. The release characteristics of ABILIFY ASIMTUFII allow plasma drug concentrations to be maintained for more than 2 months after buttock injection. After multiple administrations, the median peak-to-trough ratio of aripiprazole after ABILIFY ASIMTUFII administration is 1.3, resulting in a flat plasma concentration curve. After multiple buttock administrations of 960 mg, the time to peak concentration (Tmax) ranges from 1 to 49 days. Following a single oral administration of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactive material, respectively, are recovered from urine and feces. Less than 1% of unmetabolized aripiprazole is excreted in urine, and approximately 18% of the oral dose is recovered in feces as unmetabolized form.
After intravenous administration, aripiprazole exhibits a high steady-state volume of distribution (404 L or 4.9 L/kg), indicating its extensive extravascular distribution.
The clearance of aripiprazole is estimated at 0.8 mL/min/kg. Other studies have reported clearance rates of 3297 ± 1042 mL/hr.
Oral bioavailability is 87%. Aripiprazole is well absorbed and can be taken with or without food. Concomitant administration with a high-fat meal does not affect Cmax or AUC, but delays the Tmax of aripiprazole by 3 hours and the Tmax of dehydroaripiprazole by 12 hours.
Time to peak concentration: Peak plasma concentration: 3 to 5 hours.
The high steady-state volume of distribution of aripiprazole after intravenous administration (404 L or 4.9 L/kg) indicates its extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolites bind more than 99% to serum proteins, primarily albumin. In healthy volunteers, daily administration of 0.5 to 30 mg of aripiprazole showed a dose-dependent D2 receptor occupancy, indicating that aripiprazole can cross the blood-brain barrier. For more complete data on the absorption, distribution, and excretion of aripiprazole (a total of 8 metabolites), please visit the HSDB record page. Metabolites/Metabolites Aripiprazole is primarily metabolized via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies have shown that CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominantly circulating drug component. At steady state, the active metabolite dehydroaripiprazole accounts for approximately 40% of the area under the plasma concentration-time curve (AUC) of aripiprazole. Aripiprazole is extensively metabolized in the liver via dehydrogenation, hydroxylation, and N-dealkylation by cytochrome P-450 (CYP) 2D6 and 3A4 isoenzymes. The major active metabolite, dehydroaripiprazole, has a similar affinity for the D2 receptor to the parent compound, accounting for approximately 40% of the area under the plasma concentration-time curve (AUC) of aripiprazole. Steady-state plasma concentrations of both aripiprazole and dehydroaripiprazole are reached within 14 days. The activity of ABILIFY is primarily attributed to the parent drug aripiprazole, followed by its major metabolite, dehydroaripiprazole. Studies have shown that dehydroaripiprazole has a similar affinity for the D2 receptor to the parent drug, and its plasma exposure accounts for 40% of the parent drug exposure.
Known metabolites of aripiprazole include dehydroaripiprazole, 4-[(2-oxo-3,4-dihydro-1H-quinoline-7-yl)oxy]butyraldehyde, 4-hydroxyaripiprazole, and 2,3-dichlorophenylpiperazine.
Aripiprazole is primarily metabolized via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominantly circulating drug component. At steady state, the active metabolite dehydroaripiprazole accounts for approximately 40% of the plasma AUC of aripiprazole (RxList, A308).
Elimination pathway: Less than 1% of unchanged aripiprazole is excreted in the urine, and approximately 18% of the oral dose is excreted unchanged in the feces.
Half-life: 75–146 hours

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Biological half-life
The mean elimination half-lives of aripiprazole and dehydroaripiprazole are approximately 75 hours and 94 hours, respectively. For individuals with poor CYP2D6 metabolism, the half-life of aripiprazole is 146 hours, and these patients should receive half the normal dose. Other studies have reported a half-life of aripiprazole of 61.03 ± 19.59 hours and a half-life of its active metabolite of 279 ± 299 hours.
The mean elimination half-lives of aripiprazole and dehydroaripiprazole are approximately 75 hours and 94 hours, respectively.

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Oral absorption: In healthy volunteers (n=6), the Cmax of oral aripiprazole (OPC-14597) (10 mg) was 17 ng/mL (Tmax=3 h), and the absolute oral bioavailability was 87% (with no significant first-pass metabolism)[2].
Intravenous pharmacokinetics: In male Sprague-Dawley rats, the plasma clearance of intravenously administered aripiprazole (OPC-14597) (2 mg/kg) was 12 mL/min/kg, the steady-state volume of distribution (Vss) was 4.2 L/kg, and the half-life was 75 hours (due to the high tissue binding rate, the half-life is relatively long) [3]
-Metabolism and excretion: Aripiprazole (OPC-14597) is mainly metabolized by CYP2D6 and secondarily by CYP3A4 to generate dehydroaripiprazole (the active ingredient, with a Ki value of 0.5 nM for D₂). In the human body, 60% of the dose is excreted in feces (metabolites) within 72 hours, 30% in urine, and <1% is excreted unchanged [4]
- Tissue distribution: In male beagle dogs, the brain/plasma ratio was 4.8 2 hours after oral administration of aripiprazole (OPC-14597) (1 mg/kg), indicating that it has high blood-brain barrier penetration [3]

Toxicity Summary
Identification and Uses: Aripiprazole intramuscularly is used to treat acute mania associated with schizophrenia or bipolar disorder (mixed or manic) in adults, suitable for patients who require intramuscular antipsychotic medication to rapidly control behaviors that interfere with diagnosis and treatment (e.g., threatening behaviors, escalating or extremely distressing behaviors, self-destructive behaviors). Aripiprazole orally is used to treat acute irritability associated with autism. Aripiprazole orally may be used as adjunctive therapy to treat acute episodes of major depressive disorder in adults. Aripiprazole orally may be used as monotherapy or in combination with lithium or valproate to treat acute manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) in adults and children aged 10–17 years. This drug may also be used orally as monotherapy or in combination with lithium or valproate for maintenance treatment of bipolar I disorder in adults and children aged 10–17 years. Aripiprazole orally is used for the acute and maintenance treatment of schizophrenia in adults and adolescents aged 13–17 years. Human Exposure and Toxicity: Antipsychotic medications, including aripiprazole, have been reported to cause a potentially fatal symptom cluster, sometimes referred to as neuroleptic malignant syndrome (NMS). Two suspected cases of NMS, both occurring during aripiprazole treatment, have been documented in the premarketing global clinical database. Clinical manifestations of NMS include high fever, muscle rigidity, altered mental status, and autonomic dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and arrhythmias). Other signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Elderly patients with dementia-related psychosis receiving antipsychotic medication have an increased risk of death. In short-term studies for major depressive disorder (MDD) and other mental illnesses, antidepressants increased the risk of suicidal ideation and behavior (suicidal tendencies) in children, adolescents, and young adults compared to placebo. Animal Studies: In female mice, daily doses of 3 to 30 mg/kg increased the incidence of pituitary adenomas, mammary adenocarcinomas, and adenoacanthomas. Female rats were orally administered aripiprazole at doses of 2, 6, and 20 mg/kg/day from 2 weeks prior to mating until day 7 of gestation. Estrogenic cycle disturbances and increased corpus luteum were observed in all dose groups, but no impairment of fertility was observed. Increased preimplantation embryo loss was observed in the 6 mg/kg and 20 mg/kg dose groups, and decreased fetal weight was observed in the 20 mg/kg dose group. During organogenesis, pregnant rabbits were orally administered aripiprazole at doses of 10, 30, and 100 mg/kg/day. Decreased feed intake and increased abortion rate were observed in the 100 mg/kg dose group. Treatment resulted in increased fetal mortality (100 mg/kg), decreased fetal weight (30 and 100 mg/kg), increased incidence of skeletal malformations (sternal fusion in the 30 and 100 mg/kg dose groups), and minor skeletal variations (100 mg/kg). Aripiprazole and its metabolite (2,3-DCPP) exhibited chromosomal fragmentation induction in CHL cells in in vitro chromosomal aberration assays, regardless of metabolic activation. The metabolite 2,3-DCPP increased chromosomal number abnormalities in CHL cells in vitro, even without metabolic activation. A positive response was observed in a mouse micronucleus assay, but this response was confirmed to be due to a mechanism unrelated to humans. The antipsychotic activity of aripiprazole may derive from its antagonistic effects on D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 receptor antagonism alleviates positive symptoms of schizophrenia, while 5-HT2A receptor antagonism alleviates negative symptoms. Aripiprazole has high affinity for dopamine D2 and D3 receptors, 5-HT1A and 5-HT2A receptors, and moderate affinity for dopamine D4 receptors, 5-HT2C and 5-HT7 receptors, α1-adrenergic receptors, and histamine H1 receptors. It also has moderate affinity for the 5-HT reuptake pump. Aripiprazole has no significant affinity for cholinergic muscarinic receptors. Aripiprazole functions as a partial agonist of dopamine D2 and 5-HT1A receptors, and an antagonist of 5-HT2A receptors.

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Interactions
Substrates of hepatic microsomal enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; pharmacokinetic interactions are unlikely.

Antihypertensive Drugs: Potential Pharmacological Interactions (Additive Antihypertensive Effects)
Famotidine: Concomitant use of aripiprazole (single dose 15 mg) with a single 40 mg dose of the H2 receptor antagonist famotidine (a potent gastric acid blocker) reduces the solubility of aripiprazole, thereby decreasing its absorption rate. This results in a 37% and 21% reduction in Cmax of aripiprazole and a 13% and 15% reduction in AUC of dehydroaripiprazole, respectively. No dose adjustment of aripiprazole is required when used concurrently with famotidine.
Valproic Acid: When valproic acid (500-1500 mg/day) and aripiprazole (30 mg/day) are taken concurrently at steady state, the Cmax and AUC of aripiprazole are reduced by 25%. No dose adjustment is required when aripiprazole is used concurrently with valproic acid.
For more complete data on interactions of aripiprazole (12 in total), please visit the HSDB record page.

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Plasma protein binding: In human plasma (ultrafiltration), aripiprazole (OPC-14597) was 99% protein-bound at concentrations of 10–1000 ng/mL, and this binding was not concentration-dependent [2]
-Acute toxicity: In male ICR mice, the oral LD₅₀ of aripiprazole (OPC-14597) was >2000 mg/kg; in rats, the oral LD₅₀ was >1500 mg/kg. No death or seizures were observed at a dose of 1000 mg/kg [1]
-Chronic toxicity: In a 28-day rat study (dose: 10, 50, 200 mg/kg/day), the no adverse event observed dose (NOAEL) was 50 mg/kg/day. At a dose of 200 mg/kg/day, mild weight loss (5%) and an increase in AST (1.2-fold) were observed, but no histopathological changes were observed [3]
- Drug interactions: In humans, co-administration of aripiprazole (OPC-14597) (10 mg, orally) with paroxetine (CYP2D6 inhibitor, 20 mg/day) increased the Cmax of aripiprazole by 2.0-fold and prolonged t₁/₂ to 100 hours [4]

[1]. J Pharmacol Exp Ther. 2002 Jul;302(1):381-9.

[2]. Neuropsychopharmacology. 2003 Aug;28(8):1400-11.

[3]. Biochem Biophys Res Commun. 1999 Dec 20;266(2):560-3.

[4]. Eur J Pharmacol. 2004 Jun 16;493(1-3):75-83.

Therapeutic Uses

Antipsychotic Drugs
Aripiprazole (intramuscular injection) is used to treat acute agitation associated with schizophrenia or bipolar disorder (mixed or manic) in adults, for patients who are suitable for treatment with aripiprazole and require rapid control of behaviors that interfere with diagnosis and treatment (e.g., threatening behaviors, escalating or extremely distressing behaviors, self-destructive behaviors).
Aripiprazole (oral) is used to treat acute irritability associated with autism.
Aripiprazole (oral) is used as adjunctive therapy to treat acute episodes of major depressive disorder in adults.
For more complete data on the therapeutic uses of aripiprazole (6 types), please visit the HSDB record page.
Drug Warnings

/Black Box Warning/ Warning: Increased mortality in patients with dementia-related psychosis. Patients with dementia-related psychosis receiving antipsychotic treatment have an increased risk of death. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed a 1.6 to 1.7 times higher risk of death in the drug treatment group compared to the placebo group. These trials primarily involved patients taking atypical antipsychotic medications. In typical 10-week controlled trials, the mortality rate was approximately 4.5% in the drug treatment group and approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular diseases (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies have shown that, similar to atypical antipsychotics, treatment with conventional antipsychotics may also increase mortality. The extent to which the increased mortality observed in observational studies is attributable to antipsychotics, rather than certain patient characteristics, is currently unclear. ABILIFY (aripiperazole) is not approved for the treatment of dementia-related psychosis. /Label Contains/
/Black Box Warning/ Warning: Increased suicidal ideation and behavior. In short-term studies of major depressive disorder (MDD) and other mental illnesses, antidepressants increased the risk of suicidal ideation and behavior (suicidal tendencies) in children, adolescents, and young adults compared to placebo. Anyone considering using ABILIFY or any other antidepressant as adjunctive therapy in children, adolescents, or young adults must weigh this risk against clinical need. Short-term studies showed that antidepressants did not increase the risk of suicidal tendencies in adults 24 years of age and older compared to placebo; antidepressants reduced the risk of suicide in adults 65 years of age and older compared to placebo. Depression and certain other mental illnesses are themselves associated with an increased risk of suicide. Patients of all ages starting antidepressant therapy should be appropriately monitored and closely observed for worsening of clinical symptoms, suicidal tendencies, or abnormal changes in behavior. Family members and caregivers should be informed of the need for close monitoring and communication with the prescribing physician. ABILIFY is not approved for the treatment of childhood depression. /Included in label/
Contraindications: Known hypersensitivity to aripiprazole or any component of the formulation; such reactions range from itching/urticaria to anaphylactic shock. A 4-week, placebo-controlled clinical trial enrolled 197 children aged 10 to 17 years with bipolar disorder, demonstrating the safety and efficacy of the drug. The incidence of discontinuation due to adverse reactions was 7% in pediatric patients (aged 10 to 17 years) receiving aripiprazole and 2% in those receiving placebo. Common adverse reactions to aripiprazole in pediatric patients with bipolar disorder (incidence ≥5%, and at least twice that in the aripiprazole group compared to the placebo group) included somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, excessive salivation, and dizziness. Although the maintenance efficacy of aripiprazole in pediatric patients has not been systematically evaluated, its maintenance efficacy can be inferred from adult data and comparisons of aripiprazole pharmacokinetic parameters in adults and pediatric patients. For more complete data on drug warnings for aripiprazole (27 in total), please visit the HSDB record page.

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Pharmacodynamics
Aripiprazole exhibits high affinity for dopamine D2 and D3 receptors, and 5-HT1a and 5-HT2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), and moderate affinity for dopamine D4, 5-HT2c, and 5-HT2d receptors. It also shows moderate affinity for 5-HT7, α1-adrenergic receptors, and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and for serotonin reuptake sites (Ki = 98 nM).
Aripiprazole has high affinity for dopamine D2 and D3 receptors, 5-HT1a and 5-HT2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), and for 5-HT7, α1-adrenergic receptors, and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and for serotonin reuptake sites (Ki = 98 nM).
Aripiprazole has high affinity for serotonin D2 and D3 receptors, and for 5-HT1a and 5-HT2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively).
Aripiprazole has no significant affinity for cholinergic muscarinic receptors (IC50 1000 nM).

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Aripiprazole (OPC-14597) is a third-generation atypical antipsychotic drug that was approved by the FDA in 2002 for the treatment of schizophrenia, bipolar disorder and major depressive disorder (adjunctive therapy)[2]
- Mechanism of action: Its therapeutic effects involve dual action: 1) partial agonist of D₂ receptors (reducing positive symptoms of schizophrenia without excessively blocking dopamine); 2) 5-HT₁A receptor agonist/5-HT₂A receptor antagonist (improving negative symptoms and cognitive function)[1,3]
- Clinical efficacy: In a 6-week trial of schizophrenia (n=300), aripiprazole (OPC-14597) (15 mg/day, orally) reduced PANSS scores by 40%, compared with only a 15% reduction in the placebo group. The efficacy rate (a reduction of ≥50% in PANSS score) was 62%, compared to 28% in the placebo group [2]
- Safety: Aripiprazole (OPC-14597) had a lower risk of weight gain (≤2% in the 6-month trial) and a lower risk of extrapyramidal side effects (1.5% incidence of dystonia compared to 5% for haloperidol) [3]

C23H27CL2N3O2

448.39

447.148

C, 61.61; H, 6.07; Cl, 15.81; N, 9.37; O, 7.14

129722-12-9

Aripiprazole-d8; 1089115-06-9; Aripiprazole (1,1,2,2,3,3,4,4-d8); 1089115-04-7; Aripiprazole monohydrate; 851220-85-4; 1259305-26-4 (cavoxil)

60795

White to off-white solid powder

1.3±0.1 g/cm3

646.2±55.0 °C at 760 mmHg

139°C

344.6±31.5 °C

0.0±1.9 mmHg at 25°C

1.593

5.59

44.81

1

4

7

30

559

0

O=C1NC2=C(C=CC(OCCCCN3CCN(C4=CC=CC(Cl)=C4Cl)CC3)=C2)CC1

CEUORZQYGODEFX-UHFFFAOYSA-N

InChI=1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29)

7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.58 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.58 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 25.0 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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配方 3 中的溶解度: 2.5 mg/mL (5.58 mM) in 10% DMF 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 4 中的溶解度: 2.5 mg/mL (5.58 mM) in 10% DMF 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。

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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。