伊潘立酮 | 133454-47-4

• 物质功能分类: 原料药 - 神经系统用药 - 抗精神病药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 伊潘立酮
• 英文名称: iloperidone
• 英文别名: 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone；1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone；1-(4-{3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy}-3-methoxyphenyl)ethanone；fanapt；1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone
• CAS: 133454-47-4
• 化学式: C₂₄H₂₇FN₂O₄
• mdl: MFCD00866688
• 分子量: 426.488
• InChiKey: XMXHEBAFVSFQEX-UHFFFAOYSA-N

物化性质

• 熔点：
  118-120°C
• 沸点：
  593.7±50.0 °C(Predicted)
• 密度：
  1.204±0.06 g/cm3(Predicted)
• 闪点：
  9℃
• 溶解度：
  DMSO：可溶，5mg/mL，澄清
• 颜色/状态：
  White to off-white finely crystalline powder
• 蒸汽压力：
  8.1X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable if stored as directed; avoid strong oxidizing agents.

• 分解：
  Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides.
• 解离常数：
  pKa1 = 7.91 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.416
• 拓扑面积：
  64.8
• 氢给体数：
  0
• 氢受体数：
  7

ADMET

代谢

艾洛哌酮通过细胞色素酶在肝脏中代谢，该过程介导了O-脱烷基化（CYP3A4）、羟基化（CYP2D6）以及脱羧化和还原过程。形成的代谢物包括P89、P95和P88。P89是次要代谢物，而P95和P88是主要的代谢物。艾洛哌酮代谢物P88的亲和力通常等于或低于母体化合物。相比之下，代谢物P95仅对5-HT2A（Ki值为3.91）以及NEα1A、NEα1B、NEα1D和NEα2C受体（Ki值分别为4.7、2.7、8.8和4.7 nM）显示出亲和力。

Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively).

来源:DrugBank

代谢

伊洛哌酮主要通过羰基还原、细胞色素P-450（CYP）同工酶2D6介导的羟基化以及CYP3A4介导的O-脱甲基化进行代谢；该药物的两个主要代谢物P88和P95会进一步氧化和/或与葡萄糖醛酸结合。P88代谢物能够穿透中枢神经系统，被认为有助于药物的的抗精神病活性，而P95代谢物不易穿透中枢神经系统，主要与药物的副作用特征有关。

Iloperidone is primarily metabolized by carbonyl reduction, cytochrome P-450 (CYP) isoenzyme 2D6-mediated hydroxylation, and CYP3A4-mediated O-demethylation; the drug's two principal metabolites, P88 and P95, undergo further oxidation and/or conjugation with glucuronic acid. The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

艾洛哌酮主要通过3种生物转化途径进行代谢：羰基还原、羟基化（由CYP2D6介导）和O-脱甲基化（由CYP3A4介导）。艾洛哌酮有两种主要代谢物，P95和P88。艾洛哌酮代谢物P95在广泛代谢者（EM）的稳态血浆中占艾洛哌酮及其代谢物AUC的47.9%，而在不良代谢者（PM）中占25%。活性代谢物P88在EM和PM的总血浆暴露量中分别占19.5%和34.0%。大约7%至10%的高加索人和3%至8%的非裔美国人缺乏代谢CYP2D6底物的能力，被归类为不良代谢者（PM），其余的人是中间、广泛或超快速代谢者。与已知的CYP2D6强抑制剂（如氟西汀）联合使用Fanapt，会导致艾洛哌酮血浆暴露量增加2.3倍，因此应给予Fanapt一半的剂量。同样，CYP2D6的PM与EM相比，对艾洛哌酮的暴露更高，PM的剂量应减少一半。

Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively. Approximately 7% to 10% of Caucasians and 3% to 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of Fanapt with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3-fold increase in iloperidone plasma exposure, and therefore one-half of the Fanapt dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half.

来源:Hazardous Substances Data Bank (HSDB)

代谢

伊洛哌酮已知的人体代谢物包括：1-[4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]-2-羟基乙酮，4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基-α-甲基苯甲醇，以及1-[4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-羟基苯基]乙酮。

Iloperidone has known human metabolites that include 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-a-methylbenzene methanol, and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- propoxy]-3-hydroxyphenyl]ethanone.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

识别和使用：伊洛哌酮是一种白色至微白色的细微结晶粉末，制成口服片剂。伊洛哌酮被认为是一种非典型或第二代抗精神病药物。它用于治疗成人的精神分裂症。人类暴露和毒性：在涉及超过3210名患者的上市前试验中，记录了8名患者意外或有意过量服用伊洛哌酮，但没有致命情况。一般来说，报告的症状是已知药理作用的夸大（例如，嗜睡和镇静，心动过速和低血压）。患有与痴呆相关的精神病的老年患者使用伊洛哌酮的风险增加，因此伊洛哌酮不批准用于该人群。只有在潜在益处证明潜在风险对胎儿合理时，才应在怀孕期间使用伊洛哌酮。在妊娠第三期末暴露于抗精神病药物的婴儿在分娩后存在外周神经系统症状和/或戒断症状的风险。在这些新生儿中已有激动、肌张力增高、肌张力减退、震颤、嗜睡、呼吸困难和喂养障碍的报告。这些并发症的严重程度各不相同；在某些情况下症状是自限性的，但在其他情况下新生儿需要重症监护支持并延长住院时间。有时被称为神经阻滞剂恶性综合征（NMS）的一种潜在致命症状复合体与抗精神病药物的使用有关，包括伊洛哌酮。高血糖症，有时伴随酮症酸中毒、高渗性昏迷或死亡，也在接受非典型抗精神病药物（包括伊洛哌酮）的患者中有所报道。伊洛哌酮有两个主要代谢物，P88和P95。P88代谢物渗透中枢神经系统，被认为有助于药物的 抗精神病活性，而P95代谢物不易渗透中枢神经系统，主要与药物的副作用有关。动物研究：在小鼠和大鼠中进行了终身致癌性研究。将伊洛哌酮口服给小鼠，剂量为2.5、5.0和10 mg/kg/天，给大鼠的剂量高达16 mg/kg/天。仅在最低剂量（2.5 mg/kg/天）处理的女鼠中，恶性乳腺肿瘤的发生率增加。大鼠中没有与治疗相关的肿瘤增加。研究了伊洛哌酮代谢物P95在大鼠中的致癌潜力，雄性口服剂量高达200 mg/kg/天，雌性高达250 mg/kg/天。药物相关肿瘤变化发生在垂体（垂体远侧部腺瘤）和胰腺（胰岛细胞腺瘤）。伊洛哌酮还引起了发育毒性，但在大鼠和兔中不是致畸的。在器官形成期，给怀孕大鼠高达64 mg/kg/天的伊洛哌酮。最高剂量导致早期宫内死亡增加和胎儿存活率降低；这个剂量还引起了母体毒性。在类似的研究中，器官形成期给怀孕兔高达25 mg/kg的伊洛哌酮。最高剂量导致早期宫内死亡增加和胎儿存活率降低；这个剂量还引起了母体毒性。在给大鼠在受孕前或从妊娠第17天开始并在断奶期结束的伊洛哌酮的附加研究中，引起了不良反应生殖效应，包括延长妊娠和分娩，增加死产率，增加胎儿内脏变异的发生率，减少胎儿和幼崽的体重，以及减少产后幼崽的存活率。药物对存活的幼崽的神经行为或生殖发育没有影响。在一项研究中，给雄性和雌性大鼠12和36 mg/kg的伊洛哌酮，降低了生育能力。伊洛哌酮在Ames试验和体内小鼠骨髓以及大鼠肝脏微核试验中呈阴性。伊洛哌酮在体外中国仓鼠卵巢（CHO）细胞中诱导染色体畸变，这些浓度也引起了一些细胞毒性。

IDENTIFICATION AND USE: Ilperidone is a white to off-white finely crystalline powder formulated into oral tablets. Iloperidone is considered an atypical or second-generation antipsychotic agent. It is used for the treatment of adults with schizophrenia. HUMAN EXPOSURE AND TOXICITY: In premarketing trials involving over 3210 patients, accidental or intentional overdose of iloperidone was documented in 8 patients with no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension). Elderly patients with dementia-related psychosis treated with iloperidone are at an increased risk of death and therefore iloperidone is not approved for use in that population. Iloperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including iloperidone. Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has also been reported in patients receiving atypical antipsychotic agents, including iloperidone. Iloperidone has two predominate metabolites, P88 and P95. The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug. ANIMAL STUDIES: Lifetime carcinogenicity studies were conducted in mice and rats. Iloperidone was administered orally at doses of 2.5, 5.0, and 10 mg/kg/day to mice and up to 16 mg/kg/day to rats. There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats. The carcinogenic potential of iloperidone metabolite P95 was studied in rats at oral doses up to 200 mg/kg/day in males and up to 250 mg/kg/day in females. Drug-related neoplastic changes occurred in the pituitary gland (pars distalis adenoma) and in the pancreas (islet cell adenoma). Iloperidone also caused developmental toxicity, but was not teratogenic in rats and rabbits. Pregnant rats were given up to 64 mg/kg/day of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. In a similar study, pregnant rabbits were given up to 25 mg/kg of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. Additional studies in rats given iloperidone either pre-conception or from day 17 of gestation and continuing through weaning caused adverse reproductive effects including prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

肝脏测试异常在长期使用伊洛哌酮治疗的患者中发生在1%到3%，但安慰剂治疗和对照药物也有类似的报告率。ALT（肝酶）升高通常是轻微的、暂时的，并且通常即使在不修改剂量或停药的情况下也会解决。目前没有已发表的报告中提到伊洛哌酮治疗导致的具有症状或黄疸的临床明显肝损伤。

Liver test abnormalities occur in 1% to 3% of patients on long term therapy with iloperidone, but similar rates are reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and usually resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to iloperidone therapy.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：伊洛哌酮

Compound:iloperidone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

从胃肠道吸收良好，Cmax在2-4小时内达到。在服用艾洛哌酮后3-4天达到稳态浓度。片剂与口服溶液的相对生物利用度为96%。积累以可预测的方式发生。

Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion.

来源:DrugBank

吸收、分配和排泄

• 消除途径

肾脏（其中小于1%的伊洛哌酮以原形排泄）。

Renal (in which <1% of iloperidone is excreted unchanged).

来源:DrugBank

吸收、分配和排泄

• 分布容积

表观分布容积 Vd = 1340-2800 升

Apparent Vd = 1340-2800 L

来源:DrugBank

吸收、分配和排泄

• 清除

明显的清除率（清除率/生物利用度）= 47-102 L/h.

Apparent clearance (clearance/bioavilability) = 47-102 L/h.

来源:DrugBank

吸收、分配和排泄

伊洛哌酮的表观清除率（清除率/生物利用度）为47至102升/小时，表观分布容积为1340至2800升。在治疗浓度下，血浆中游离的伊洛哌酮比例大约为3%，而每个代谢物（P88和P95）的比例大约为8%。

Iloperidone has an apparent clearance (clearance/bioavailability) of 47 to 102 L/hr, with an apparent volume of distribution of 1340 to 2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is approximately 3% and of each metabolite (P88 and P95) it is approximately 8%.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  F,T
• 安全说明：
  S16,S36/37,S45
• 危险类别码：
  R11,R23/24/25,R39/23/24/25
• WGK Germany：
  1,3
• 海关编码：
  2934999090
• 危险品运输编号：
  UN2811 - class 6.1 - PG 3 - EHS - Toxic solids, organic, n.o.s., HI: all
• RTECS号：
  KM5777850
• 危险标志：
  GHS06
• 危险性描述：
  H301,H413
• 储存条件：
  -20°C冷冻储存，置于惰性气体保护下

SDS

: Iloperidone
产品名称
: Cerilliant
1.2 鉴别的其他方法
无数据资料
1.3 有关的确定了的物质或混合物的用途和建议不适合的用途
仅用于研发。不作为药品、家庭或其它用途。

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模块 2. 危险性概述
2.1 GHS-分类
易燃液体 (类别 2)
急性毒性, 经口 (类别 3)
急性毒性, 吸入 (类别 3)
急性毒性, 经皮 (类别 3)
特异性靶器官系统毒性（一次接触） (类别 1)
2.2 GHS 标记要素，包括预防性的陈述
象形图
警示词 危险
危险申明
H225 高度易燃液体和蒸气
H301 吞咽会中毒
H311 皮肤接触会中毒
H331 吸入会中毒。
H370 对器官造成损害。
警告申明
预防
P210 远离热源、火花、明火和热表面。- 禁止吸烟。
P233 保持容器密闭。
P240 容器和接收设备接地/等势连接。
P241 使用防爆的电气/ 通风/ 照明 设备。
P242 只能使用不产生火花的工具。
P243 采取防止静电放电的措施。
P260 不要吸入粉尘/ 烟/ 气体/ 烟雾/ 蒸汽/ 喷雾。
P264 操作后彻底清洁皮肤。
P270 使用本产品时不要进食、饮水或吸烟。
P271 只能在室外或通风良好之处使用。
P280 戴防护手套/穿防护服/戴护目镜/戴面罩.
响应
P301 + P310 如果吞下去了: 立即呼救解毒中心或医生。
P303 + P361 + P353 如皮肤(或头发)沾染：立即去除/ 脱掉所有沾染的衣服。用水清洗皮肤/
淋浴。
P304 + P340 如吸入: 将患者移到新鲜空气处休息，并保持呼吸舒畅的姿势。
P307 + P311 如接触到：呼叫解毒中心或医生。
P322 具体措施(见本标签上提供的急救指导)。
P330 漱口。
P361 立即去除/脱掉所有沾染的衣服。
P363 沾染的衣服清洗后方可重新使用。
P370 + P378 火灾时： 用干的砂子，干的化学品或耐醇性的泡沫来灭火。
储存
P403 + P233 存放于通风良的地方。 保持容器密闭。
P403 + P235 存放在通风良好的地方。保持低温。
P405 存放处须加锁。
处置
P501 将内容物/ 容器处理到得到批准的废物处理厂。
2.3 其它危害物 - 无

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模块 3. 成分/组成信息
3.2 混合物
组分 分类 浓度或浓度范围
Methanol
化学文摘登记号(CA 67-56-1 Flam. Liq. 2; Acute Tox. 3; 50 - 100 %
S No.) 200-659-6 STOT SE 1; H225, H301,
EC-编号 603-001-00-X H311, H331, H370
索引编号 01-2119433307-44-XXXX
注册号
如需在本章节中提及的H类告知和R类描述的全部文字说明,请见第16章节.

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模块 4. 急救措施
4.1 必要的急救措施描述
一般的建议
请教医生。 向到现场的医生出示此安全技术说明书。
吸入
如果吸入,请将患者移到新鲜空气处。 如呼吸停止,进行人工呼吸。 请教医生。
皮肤接触
用肥皂和大量的水冲洗。 立即将患者送往医院。 请教医生。
眼睛接触
用水冲洗眼睛作为预防措施。
食入
禁止催吐。 切勿给失去知觉者通过口喂任何东西。 用水漱口。 请教医生。
4.2 主要症状和影响，急性和迟发效应
据我们所知，此化学，物理和毒性性质尚未经完整的研究。
如吞服甲醇可能致命或致盲。, 不能制成无毒性的。, 摄入的影响可包括：, 恶心, 头痛, 呕吐, 消化系统失调,
头晕, 虚弱, 混乱
4.3 及时的医疗处理和所需的特殊处理的说明和指示
无数据资料

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模块 5. 消防措施
5.1 灭火介质
灭火方法及灭火剂
用水雾,抗乙醇泡沫,干粉或二氧化碳灭火。
5.2 源于此物质或混合物的特别的危害
无数据资料
5.3 给消防员的建议
如必要的话,戴自给式呼吸器去救火。
5.4 进一步信息
用水喷雾冷却未打开的容器。

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模块 6. 泄露应急处理
6.1 作业人员防护措施、防护装备和应急处置程序
戴呼吸罩。 避免吸入蒸气、烟雾或气体。 保证充分的通风。 移去所有火源。 人员疏散到安全区域。
谨防蒸气积累达到可爆炸的浓度。蒸气能在低洼处积聚。
6.2 环境保护措施
如能确保安全，可采取措施防止进一步的泄漏或溢出。 不要让产品进入下水道。
6.3 泄漏化学品的收容、清除方法及所使用的处置材料
围堵溢出，用防电真空清洁器或湿刷子将溢出物收集起来，并放置到容器中去,根据当地规定处理(见第13部
分)。
6.4 参考其他部分
丢弃处理请参阅第13节。

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模块 7. 操作处置与储存