leurosidine | 865-21-4

• 物质功能分类: 分析化学 - 标准品
• 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: leurosidine
• 英文别名: methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,15S,17R)-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]-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
• CAS: 865-21-4
• 化学式: C₄₆H₅₈N₄O₉
• 分子量: 810.988
• InChiKey: JXLYSJRDGCGARV-DVOOFMKJSA-N

物化性质

• 熔点：
  211-216°
• 比旋光度：
  D23 -32° (c = 0.88 in methanol)
• 沸点：
  755.65°C (rough estimate)
• 密度：
  1.1325 (rough estimate)
• 溶解度：
  可溶于氯仿、二氯甲烷、二甲基亚砜、甲醇
• 颜色/状态：
  Solvated needles from methanol
• 蒸汽压力：
  1.03X10-27 mm Hg at 25 °C (est)
• 稳定性/保质期：

  SOLN MAY BE STORED IN REFRIGERATOR FOR PERIODS OF 30 DAYS WITHOUT SIGNIFICANT LOSS OF POTENCY /VINBLASTINE SULFATE/

• 旋光度：
  Specific optical rotation: -32 deg at 23 °C/D ( c = 0.88 in methanol)
• 分解：
  When heated to decomposition it emits toxic fumes of oxides of nitrogen.
• 解离常数：
  pKa1 = 5.4; pKa2 = 7.4

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  59
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  154
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

长春碱据报道在体内被广泛代谢，主要在肝脏，代谢为去乙酰长春碱，后者在重量基础上比原化合物更活跃。

Vinblastine is reported to be extensively metabolized, primarily in the liver, to desacetylvinblastine, which is more active than the parent compound on a weight basis.

来源:Hazardous Substances Data Bank (HSDB)

代谢

由于主要的排泄途径可能是通过胆汁系统，当存在肝脏排泄功能不足时，这种药物的毒性可能会增加。已证实长春花碱的代谢是通过肝脏细胞色素P450同工酶CYP 3A亚家族介导的。在肝功能不全的患者或同时服用这些同工酶的强效抑制剂（如红霉素）的患者中，这种代谢途径可能会受损。

Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic excretory insufficiency. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes such as erythromycin.

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，在母体抗肿瘤药物治疗期间，母乳喂养是禁忌的。由于长春碱治疗药物半衰期长，可能在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。在怀孕期间接受化疗的妇女更可能难以哺乳她们的婴儿。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：一名在怀孕第二季度被诊断为霍奇金淋巴瘤的妇女在第三季度怀孕期间接受了3轮化疗，并在产后4周恢复了化疗。在重新开始后的16周内，在化疗前15至30分钟和化疗后收集了乳汁样本。治疗方案包括每2周一次，2小时内给予多柔比星40毫克，博来霉素16单位，长春碱9.6毫克和达卡巴嗪600毫克。将该患者的乳汁微生物群和代谢概况与8名未接受化疗的健康妇女进行比较。患者的乳汁微生物群与健康妇女明显不同，Acinetobacter sp., Xanthomonadacae 和 Stenotrophomonas sp. 增加，而 Bifidobacterium sp. 和 Eubacterium sp. 减少。在接受治疗的妇女的乳汁中，许多化学成分也有显著差异，尤其是DHA和肌醇减少。 对在第二或第三季度怀孕期间在一个中心接受癌症化疗的74名妇女进行了电话随访研究，以确定她们产后是否成功进行母乳喂养。只有34%的妇女能够完全母乳喂养她们的婴儿，66%的妇女报告遇到母乳喂养困难。这与其他22位在怀孕期间被诊断但在未接受化疗的母亲中91%的母乳喂养成功率相比。其他具有统计学意义的相关性包括：1. 有哺乳困难的母亲平均接受了5.5个周期的化疗，而没有困难的母亲平均接受了3.8个周期；2. 有哺乳困难的母亲在怀孕期间平均提前3.4周接受了她们的第一个化疗周期。在接受了含有长春新碱方案的6名妇女中，有5名遇到了哺乳困难。

◉ 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 vinblastine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased. A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 6 women who received a vincristine-containing regimen, 5 had breastfeeding difficulties.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

在同时服用已知抑制肝细胞色素P450同工酶CYP 3A亚家族药物代谢的药物的患者，或肝功能不全的患者中应谨慎。与这种代谢途径的抑制剂同时使用长春碱硫酸盐可能会导致副作用更早出