methyl (1R,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 (1R,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: 824.971
• InChiKey: OGWKCGZFUXNPDA-FUOYXGTBSA-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... (3)H长春新碱后，72小时内，69%的放射性活性在粪便中回收，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是完整的。胆瘘患者表现出完整的药物（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

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