methyl (10S,11R,12R)-11-acetyloxy-12-ethyl-4-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate | 57-22-7

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 长春花生物碱
• 英文名称: methyl (10S,11R,12R)-11-acetyloxy-12-ethyl-4-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
• CAS: 57-22-7
• 化学式: C₄₆H₅₆N₄O₁₀
• 分子量: 825.0
• InChiKey: OGWKCGZFUXNPDA-DLBZMDDPSA-N

物化性质

• 熔点：
  211-216 ºC
• 比旋光度：
  D25 +17°; D25 +26.2° (ethylene chloride)
• 沸点：
  761.92°C (rough estimate)
• 密度：
  1.1539 (rough estimate)
• 溶解度：
  溶于氯仿、二氯甲烷、乙酸乙酯、DMSO、丙酮等。
• 物理描述：
  Vincristine appears as a white crystalline solid. Melting point 218°C. Used as an antineoplastic.
• 颜色/状态：
  Blades from methanol
• 稳定性/保质期：

  STERILE SOLN IN EITHER H2O OR PHYSIOLOGICAL SALINE STORED IN REFRIGERATOR FOR UP TO 2 WK WITHOUT SIGNIFICANT LOSS OF POTENCY

• 旋光度：
  Specific optical rotation: +17 deg at 25 °C/D; +26.2 deg at 25 °C/D (ethylene chloride); max absorption (ethanol): 220, 255, 296 nm (log molar absorptivity = 4.65, 4.21, 4.18)
• 分解：
  When heated to decomposition it emits toxic fumes of oxides of nitrogen.
• 解离常数：
  pKa: 5.0, 7.4 in 33% dimethylformamide

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  60
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  171
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

静脉注射[放射性同位素标记的]长春新碱后，72小时内，69%的放射性物质在粪便中回收，12%在尿液中回收。大约一半是以代谢物的形式存在，其紫外光谱表明长春新碱二聚体保持完整。胆瘘患者显示出完整的药物（46.5%）和代谢物（53.5%）的广泛胆汁排泄。观察结果表明，胆汁-粪便途径在排泄中占主导地位。

After iv administration of ... (3)H vincristine, 69% of radioactivity was recovered in feces and 12% in urine over 72 hr period. Approx half ... was in form of metabolites, whose UV spectrum suggested that vincristine dimer was intact. Patients with biliary fistula showed extensive biliary excretion of intact drug (46.5%) & of metabolites (53.5%). Observations suggest that biliary-fecal route ... predominate in excretion ... .

来源:Hazardous Substances Data Bank (HSDB)

代谢

长春新碱的代谢命运尚未明确确定；该药物似乎被广泛代谢，可能是在肝脏中，但代谢的程度不清楚，因为药物在体内也显然会分解。

The metabolic fate of vincristine has not been clearly determined; the drug appears to be extensively metabolized, probably in the liver, but the extent of metabolism is not clear since the drug also apparently undergoes decomposition in vivo.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

硫酸长春新碱与伊曲康唑（已知是代谢途径的抑制剂）同时给药据报道会导致神经肌肉副作用更早出现和/或增加严重程度（见不良反应）。这种相互作用被认为与抑制长春新碱的代谢有关。

Concurrent administration of vincristine sulfate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side effects (see Adverse Reactions). This interaction is presumed to be related to inhibition of the metabolism of vincristine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

口服或静脉注射苯妥英钠与包括硫酸长春新碱在内的抗肿瘤化疗方案同时给药，据报道会降低抗惊厥药物的血液水平并增加癫痫发作活动。剂量调整应基于连续的血药浓度监测。硫酸长春新碱对此相互作用的贡献尚不确定。这种相互作用可能是由苯妥英钠吸收减少以及其代谢和排泄速率增加所导致。

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vincristine sulfate has been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vincristine sulfate to this interaction is not certain. The interaction may result from reduced absorption of phenytoin and an increase in the rate of its metabolism and elimination.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

牛脑神经节苷脂对长春新碱神经毒性的影响在10天鸡胚背根神经节细胞的离体培养中进行了研究。药物的作用通过计算具有神经突起的细胞数量或单个具有神经突起的细胞中神经突起的总长度来量化。长春新碱（1至1000 pg/mL）的给药抑制了细胞的神经突起生长，而神经节苷脂（10至1000 ug/mL）以浓度依赖性的方式对抗这种抑制作用。电子显微镜揭示了长春新碱诱导神经突起中的微管碎片化和纵向错位，并显示了神经节苷脂对这种损害作用的防护。结果表明，外源性给予神经节苷脂可以减轻长春新碱在体外的神经毒性。

The effects of bovine brain gangliosides on the neurotoxicity of vincristine were investigated in dissociated cultures of dorsal root ganglion cells from 10 day chick embryos. The effects of the drugs were quantified as the numbers of neurite bearing cells or total neurite length in individual neurite bearing cells. The administration of vincristine (1 to 1000 pg/mL) inhibited neurite outgrowth from the cells, whereas gangliosides (10 to 1000 ug/mL) protected them against this inhibition in a concentration dependent manner. Electron microscopy revealed vincristine induced fragmentation and longitudinal disorientation of microtubules in neurites and showed the protection by gangliosides against such damaging effects. Results show that exogenous administration of gangliosides attenuates the neurotoxicity of vincristine in vitro.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维拉帕米已被证明能够在体外和体内克服P388白血病对长春新碱的获得性耐药。为了研究这种作用的特异性，研究了在加入维拉帕米后对长春新碱细胞毒性的影响，使用的细胞来自8名慢性淋巴细胞白血病患者的外周血淋巴细胞、一个T-急性淋巴细胞性白血病细胞系（GM 3639）的淋巴母细胞，以及8名正常健康志愿者的外周血淋巴细胞。使用差染细胞毒性分析，证明了在1 uM浓度下，维拉帕米能够增强长春新碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性，浓度为0.04-0.25 ug/L。然而，没有观察到对对照组外周血淋巴细胞的细胞毒性增强。数据表明，维拉帕米优先增强长春新碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性，但对淋巴细胞没有观察到细胞毒性的增强。

Verapamil has been shown to overcome acquired drug resistance to vincristine in P388 leukemia both in vitro and in vivo. To study the selectivity of this action, the effect of addition of verapamil on the cytotoxicity of vincristine was studied using lymphocytes from eight patients with chronic lymphocytic leukemia, lymphoblasts from a T-acute lymphoblastic leukemia cell line (GM 3639), and peripheral blood lymphocytes from eight normal healthy volunteers. Using the differential staining cytotoxicity assay, it was demonstrated that verapamil at 1 uM concentration potentiated the in vitro cytotoxicity of vincristine on chronic lymphocytic leukemia and GM 3639 cells in concentrations of 0.04-0.25 ug/L. There was however, no enhancement of cytotoxicity noted against the control peripheral blood lymphocytes. The data demonstrate that verapamil preferentially enhances the in vitro cytotoxicity of vincristine on chronic lymphocytic leukemia and GM 3639 cells but no enhancement of cytotoxicity is seen against peripheral blood lymphocytes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

保持呼吸道通畅，必要时协助通气。如果出现昏迷、抽搐、低血压和心律失常，则进行治疗。使用甲氧氯普胺治疗恶心和呕吐，使用静脉晶体液治疗胃肠炎引起的液体丢失。对于骨髓抑制，应在经验丰富的血液学家或肿瘤学家的帮助下进行治疗。外渗：立即停止输液，并通过注射器的负压尽可能多地抽回液体。然后给予以下特定治疗：在区域上放置加热垫，间歇加热24小时；抬高肢体。局部注射透明质酸酶可能有益。不要使用冰袋。/对于/去污，如果条件适当，口服活性炭。在小到中等摄入量后，如果可以迅速给予活性炭，则无需进行胃灌洗。由于这些药物的快速细胞内结合，透析和其他体外清除程序通常无效。/抗肿瘤药物/

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment: Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase may be benef