ingenol mebutate | 75567-37-2

• 物质功能分类: 生物化工
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: ingenol mebutate
• 英文别名: 3-Ingenyl angelate；2-methyl-2(Z)-butenoic acid (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl ester；2-methyl-2(Z)-butenoic acid(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl ester；(1aR,2S,5R,5 aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclpropa[e][10]annulen-6-yl (2Z)-2-methylbut-2-enoate；(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl (2Z)-2-methylbut-2-enoate；[(1S,4S,5S,6R,9S,10R,12R,14R)-5,6-dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxo-4-tetracyclo[7.5.1.01,5.010,12]pentadeca-2,7-dienyl] (Z)-2-methylbut-2-enoate
• CAS: 75567-37-2
• 化学式: C₂₅H₃₄O₆
• 分子量: 430.541
• InChiKey: VDJHFHXMUKFKET-WDUFCVPESA-N

物化性质

• 沸点：
  576.9±50.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶15mg/mL，澄清
• 颜色/状态：
  White to pale yellow crystalline powder
• 蒸汽压力：
  3.17X10-15 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions.

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

Picato没有发生代谢，因为ingenol mebutate是一种局部治疗药物，且ingenol mebutate并不抑制或诱导大多数细胞色素P450（CYP）酶。

There is no metabolism of Picato since ingenol mebutate is a topical treatment, and ingenol mebutate does not inhibit or induce a majority of the cytochrome P450 (CYP) enzymes.

来源:DrugBank

代谢

ingenol mebutate在体外在大鼠、狗、小型猪和人类的血液、皮肤匀浆和肝细胞中的代谢特性基本相似。发现ingenol mebutate在血液和皮肤匀浆中相对稳定，并在冷冻保存的肝细胞中发生广泛代谢。在大鼠、狗和小型猪的肝细胞中，主要途径是水解为ingenol，而在人类中，主要途径是ingenol mebutate的羟基化。在大鼠、狗、小型猪和人类的皮肤中，ingenol mebutate的主要重排产物是PEP015（约占26%至31%）和PEP025（约占1%至2%）；水解为ingenol的情况很少（0%至0.81%）。然而，在大鼠和小型猪经皮或静脉注射ingenol mebutate后，未检测到PEP025，PEP015的浓度低于相应ingenol mebutate的10%。

The in vitro metabolism of ingenol mebutate was qualitatively similar in blood, skin homogenates and hepatocytes of rats, dogs, minipigs and humans. Ingenol mebutate was found to be relatively stable in blood and skin homogenates, and to undergo extensive metabolism in cryopreserved hepatocytes. The major pathway in rat, dog and minipig hepatocytes was hydrolysis to ingenol, whereas the major pathway in humans was hydroxylation of ingenol mebutate. In the skin of rats, dogs, minipigs and humans, rearrangement of ingenol mebutate was predominantly to PEP015 (approximately 26% to approximately 31%) and, to a much lesser extent, PEP025 (approximately 1% to approximately 2%); hydrolysis to ingenol was minimal (0% to 0.81%). However, after topical or IV administration of ingenol mebutate to rats and minipigs, PEP025 was not detected and PEP015 was less than 10% of the corresponding ingenol mebutate concentration in the blood.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用： ingenol mebutate是一种白色至淡黄色结晶性粉末。作为药物Picato，它以凝胶形式用于外用治疗光化性角化病。人类暴露和毒性：三项健康志愿者药物学研究结果表明，ingenol mebutate凝胶具有较好的局部安全性，未见皮肤致敏、光照射或光变态反应的迹象。然而，局部过量使用可能会导致局部皮肤反应的发生率增加。动物研究：在大鼠连续28天静脉给药后，治疗相关的影响包括短暂的呼吸急促（与剂量无关）、乏力/行为抑制和食欲下降。在小鼠连续7天给药后，一只动物在60微克/千克/天的剂量下，以及所有在接受>/= 80微克/千克/天的剂量下的动物，在给药后

IDENTIFICATION AND USE: Ingenol mebutate is a white to pale yellow crystalline powder. As the drug Picato, it is used as a gel for the topical treatment of actinic keratosis. HUMAN EXPOSURE AND TOXICITY: Results from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirradiation, or photoallergic potential. However, topical overdosing could result in an increased incidence of local skin reactions. ANIMAL STUDIES: In rats given repeat IV dosing for 28 days, treatment-related effects included transient tachypnea, which was not dose-related, lethargy and/or subdued behavior and decreased food consumption. In mice dosed for 7 consecutive days, one animal receiving 60 ug/kg/day and all animals receiving >/= 80 ug/kg/day were killed prematurely after </= 4 days of dosing because of the severity of physical signs, which were dose-related. In mini-pigs, no deaths occurred at 5 ug/kg/day ingenol mebutate for 4 consecutive days or 3 ug/kg/day for 28 days. Treatment-related effects were limited to sporadic and transient subdued behavior, emesis and slightly reduced body weight gain post-dose at 2.5 ug/kg/day. An increase in embryo-fetal mortality as well as increased incidence of fetal visceral and skeletal variations was noted in pregnant rabbits exposed to ingenol mebutate intravenously. No treatment related effects on embryofetal toxicity or teratogenicity were noted after intravenous administration to pregnant rats. Ingenol mebutate was not mutagenic in an in vitro Ames test, mouse lymphoma assay, and in vivo rat micronucleus test. An in vitro Syrian hamster embryonic (SHE) cell transformation assay was positive. A 6-month repeat dose IV rat study in 154 rats found that one male and one female dosed twice weekly with 15 ug/kg had a kidney tubular adenoma and tubular hyperplasia of the kidney. A pituitary adenoma was also present in the female with the renal adenoma. At the 1-month recovery kill, one male had a thyroid follicular cell carcinoma.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：外用 ingenol mebutate 在母乳喂养期间尚未进行研究。然而，在局部给药后，血清浓度无法检测到，因此母乳喂养预计不会导致哺乳婴儿接触到该药物。如果母亲需要使用 ingenol mebutate，这并不是停止母乳喂养的理由。不要将 ingenol mebutate 应用于乳房或乳头，并确保婴儿的皮肤不直接接触到已治疗的皮肤区域。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Topical ingenol mebutate has not been studied during breastfeeding. However, after topical administration, serum concentrations were undetectable, so breastfeeding is not expected to result in exposure of the breastfed infant. If ingenol mebutate is required by the mother, it is not a reason to discontinue breastfeeding. Do not apply ingenol mebutate to the breast or nipple and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者身体前倾或将其置于左侧（如果可能，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

ingenol mebutate是一种局部治疗，因此系统吸收量小于0.1纳克/毫升。

Since ingenol mebutate is a topical treatment, the systemic absorption is less than 0.1 ng/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

ingenol mebutate是一种局部治疗，因此没有消除途径。

There is no route of elimination since ingenol mebutate is a topical treatment.

来源:DrugBank

吸收、分配和排泄

• 分布容积

ingenol mebutate是一种局部治疗，因此没有分布容积量。

There is no volume of distribution quantity since ingenol mebutate is a topical treatment.

来源:DrugBank

吸收、分配和排泄

• 清除

ingenol mebutate是一种外用治疗方法,因此没有清除量。

There is no clearance quantity since ingenol mebutate is a topical treatment.

来源:DrugBank

吸收、分配和排泄

血浆清除率和稳态分布体积（稳态）在人体中是使用基于体重的简单异速相关估计的。使用一室模型，具有一级吸收和消除动力学，估计最大拟定临床剂量2微克/千克/天的经皮给药会在血液中产生低于0.1纳克/毫升的LLOQ的 ingenol mebutate 水平。稳态时的血液清除率和分布体积预计将从大约0.22到1.01升/小时/千克和大约0.61升/千克， respectively. 吸收速率常数和局部生物利用度预计分别为0.0277小时^-1和0.21%， respectively. 对于2微克/千克/天的局部剂量，预计人体血液Tmax为2小时，Cmax为0.107皮克/毫升。为了产生可检测的血液水平，人体至少需要2000微克/千克/天的局部剂量。

Plasma clearance and volume of distribution (steady-state) in humans were estimated using a simple allometric correlation based on body weight. Using a one-compartment model with first-order absorption and elimination kinetics, it was estimated that dermal administration of the maximum intended clinical dose of 2 ug/kg/day would produce levels of ingenol mebutate in the blood below the LLOQ of 0.1 ng/mL. Blood clearance and volume of distribution at steady-state were predicted to range from approximately 0.22 to 1.01 L/hr/kg and approximately 0.61 L/kg, respectively. The absorption rate constant and topical bioavailability was projected to be 0.0277 hours-1 and 0.21%, respectively. A human blood Tmax of 2 hours and Cmax of 0.107 pg/mL were predicted for a 2 ug/kg/day topical dose. A minimum topical dose of 2000 ug/kg/day to humans would be required produce detectable blood levels.

来源:Hazardous Substances Data Bank (HSDB)

SDS

制备方法与用途

生物活性

Ingenol Mebutate 是 Euphorbia peplus 中的活性成分，为 PKC 的调节剂。其对 PKC-α、PKC-β、PKC-γ、PKC-δ 和 PKC-ε 的 Ki 值分别为 0.3 nM、0.105 nM、0.162 nM、0.376 nM 和 0.171 nM。

靶点	Ki值（nM）
PKC-β	0.105
PKC-γ	0.162
PKC-ε	0.171
PKC-α	0.3
PKC-δ	0.376

体外研究

Ingenol Mebutate (Ingenol 3-angelate) 是 Euphorbia peplus 的活性成分，作为强效 PKC 激活剂，其对 PKC-α、PKC-β、PKC-γ、PKC-δ 和 PKC-ε 的 Ki 值分别为 0.3 nM、0.105 nM、0.162 nM、0.376 nM 和 0.171 nM。此外，Ingenol Mebutate 在 WEHI-231 细胞中的 EC50 值分别为 PKC-α (13 ± 2.4 nM)、PKC-βI (4.37 ± 0.4 nM)、PKC-βII (10.5 ± 2.2 nM)、PKC-δ (38.6 ± 2.9 nM) 和 PKC-ε (1.08 ± 0.01 nM)，在 HOP-92 细胞中的 EC50 值分别为 PKC-α (198 ± 12.5 nM)、PKC-βI (69.1 ± 8.2 nM)、PKC-ε (4.6 ± 0.4 nM)，在 Colo-205 细胞中的 EC50 值分别为 PKC-α (635 ± 245 nM)、PKC-βI (146 ± 35 nM)、PKC-δ (4.7 ± 0.7 nM) 和 PKC-ε (1.1 ± 0.5 nM)。Ingenol Mebutate 还在 Colo205-R 细胞中表现出对 Ingenol Mebutate 的高度耐受性（IC50 >10 μM），而其亲代细胞 Colo205-S 对 Ingenol Mebutate 更敏感。

化学性质

Ingenol Mebutate 是一种白色粉末，可溶于甲醇、乙醇和 DMSO 等有机溶剂。它来源于大戟科(Euphorbia)植物的全草。

用途

用于含量测定/鉴定/药理实验等。

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