Vincristine (free base) | 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: Vincristine (free base)
• 英文别名: methyl 11-acetyloxy-12-ethyl-4-(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-UHFFFAOYSA-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

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：大多数来源认为，在母亲抗肿瘤药物治疗期间，母乳喂养是禁忌的。由于长春新碱的半衰期较长，可能在长春新碱治疗后恢复母乳喂养是不切实际的。化疗可能会不利地影响母乳的正常微生物组和化学成分。 ◉ 对哺乳婴儿的影响：在一个4个月大的婴儿中，中性粒细胞减少可能是由于母亲在连续6周每周静脉注射800毫克环磷酰胺、2毫克长春新碱静脉注射和每天30毫克泼尼松龙口服的最后9天由环磷酰胺引起的。中性粒细胞减少持续至少12天，并伴有短暂的腹泻。长春新碱对中性粒细胞减少的贡献无法确定。 一名妇女在怀孕27周时被诊断出患有B细胞淋巴瘤。在34 4/7周时诱导分娩，并在分娩后第2天开始使用标准的利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松龙的21天周期治疗方案，剂量未明确说明。她在每个周期的前10天抽吸并丢弃她的乳汁，并给她的婴儿喂食捐赠的乳汁，然后在下一个治疗周期前的剩余10天母乳喂养她的婴儿。根据使用大约3个长春新碱半衰期确定的10天母乳喂养禁欲期。在完成4个周期的化疗后，她的婴儿据报道健康无任何并发症地发育。 ◉ 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:Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It is probably impractical to resume breastfeeding after vincristine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. ◉ Effects in Breastfed Infants:In a 4-month-old, neutropenia was probably caused by cyclophosphamide in a mother 9 days after the last of 6 weekly doses of 800 mg cyclophosphamide intravenously, 2 mg vincristine intravenously and daily doses of 30 mg of prednisolone orally. Neutropenia persisted at least 12 days and was accompanied by a brief episode of diarrhea. The contribution of vincristine to the neutropenia cannot be determined. A woman was diagnosed with B-cell lymphoma at 27 weeks of pregnancy. Labor was induced at 34 4/7 weeks and treatment was begun with a standard regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in unspecified doses on a 21-day cycle, starting on day 2 postpartum. She pumped and discarded her milk and fed her infant donor milk for the first 10 days of each cycle and then breastfed her infant for the remaining 10 days before the next treatment cycle. The 10-day period of breastfeeding abstinence was determined by using about 3 half-lives of vincristine. After completion of 4 cycles of chemotherapy, her infant was reportedly healthy and developing without any complications. ◉ 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

• 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分离培养中进行了研究。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）以浓度依赖性方式保护细胞免受这种抑制。电子显微镜揭示了长春新碱诱导神经突起中的微管断裂和纵向定向错误，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，本研究探讨了在慢性淋巴细胞白血病患者淋巴细胞、T急性淋巴细胞白血病细胞系（GM 3639）和8名正常健康志愿者的外周血淋巴细胞中添加维拉帕米对长春新碱细胞毒性的影响。使用差异染色细胞毒性分析，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，对于对照组的外周血淋巴细胞，并未观察到细胞毒性的增强。数据显示，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，但对于外周血淋巴细胞并未看到细胞毒性的增强。

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)

吸收、分配和排泄

中枢神经系统白血病在接受长春新碱治疗且血液学缓解的患者中的发展被解释为证据，表明长春新碱很难通过血脑屏障。长春新碱可以以比静脉给药大几倍的剂量注入肿瘤的动脉血液供应中，而毒性相当；因此，局部吸收或破坏非常迅速。长春花生物碱主要通过肝脏排入胆汁。

Development of CNS leukemia in patients receiving vinc