methyl (1S,10R,11S,12S)-11-acetyloxy-12-ethyl-4-[(13R,15R,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 | 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: methyl (1S,10R,11S,12S)-11-acetyloxy-12-ethyl-4-[(13R,15R,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: 811.0
• InChiKey: JXLYSJRDGCGARV-PFZUDZJTSA-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：
  Crystallizes as hydrate, mp 284-285 °C. Specific optical rotation = - 28 deg at 26 °C/D ( c = 1.01 in methanol); UV max (Methanol): 212, 262, 282, 292 nm (log epsilon = 4.75, 4.28, 4.22, 4,18). Very slightly soluble in ethanol. Practically insoluble in ether. One part is soluble in 10 parts of water, 50 parts of chloroform /Sulfate/
• 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

长春碱据报道在肝脏中广泛代谢，主要代谢为去乙酰长春碱，后者在重量基础上比母体化合物更活跃。

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。已经证明，长春花碱类药物的代谢是通过肝脏细胞色素P450同工酶中的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

• 相互作用

在同时服用已知抑制肝脏细胞色素P450同工酶CYP 3A亚家族药物代谢的患者，或在肝功能不良的患者中，应谨慎使用。硫酸长春碱与这一代谢途径的抑制剂同时使用可能会导致副作用更早出现和/或增加严重性。

Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects.

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碱在内的抗肿瘤化疗方案的联合应用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。

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

评估长春碱和重组干扰素-β之间的潜在协同作用，使用中效分析法。组合指数的计算显示出小于1的值（表示协同作用），在四种不同的肾细胞癌细胞系中，药物引起的生长抑制的广泛范围内。观察到的协同程度无法从形态、倍增时间或肾细胞癌细胞系对长春碱和重组干扰素-β的相对敏感性预测。长春碱与重组干扰素-β在组合中的最佳比例似乎接近于每种药物产生50%生长抑制的浓度的比例。尽管在培养介质中同时存在长春碱和重组干扰素-β并不是展示协同效应所必需的，但重组干扰素-β的最小暴露时间确定为7天。在2.25 ng/mL重组干扰素-β中生长4天后，肾细胞癌细胞系对放射性标记长春碱的摄取增加，但排出没有增加。中效分析法可以独立于长春碱和重组干扰素-β的作用机制，并且给出了在广泛药物效果范围内潜在协同相互作用的指示。这种方法可能在选择干扰素和抗肿瘤药物组合进行临床研究时证明是有用的。

Potential synergistic interactions between vinblastine and recombinant interferon-beta were assessed using median effect analysis. Calculation of the combination index demonstrated values less than 1 (indicating synergy) over a wide range of drug induced growth inhibition for each of four different renal carcinoma cell lines. The degree of synergy observed could not be predicted from the morphology, doubling time, or relative sensitivity of the renal carcinoma cell lines to vinblastine and recombinant interferon-beta. The optimal ratio of vinblastine to recombinant interferon-beta in the combination appeared to be close to the ratio of the concn of each agent which yielded a 50% inhibition of growth. Although simultaneous presence of vinblastine and recombinant interferon-beta in the culture medium was not required to demonstrate a synergistic effect, the minimum exposure time for recombinant interferon-beta was determined to be 7 days. The uptake but not the egress of tritiated vinblastine into renal carcinoma cell line cells was enhanced after growth for 4 days in 2.25 ng/mL of recombinant interferon-beta. Median effect analysis can be shown to be independent of the mechanism of action of vinblastine and recombinant interferon-beta and gives an indication of potential synergistic interactions over a wide range of drug effects. This method may prove useful in the selection of combinations of IFNs and antitumor drugs for clinical study.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一名HIV感染者在接受了ABVD（多柔比星、博来霉素、长春碱、达卡巴嗪）化疗和基于洛匹那韦-利托那韦的抗逆转录病毒治疗后，用于治疗IVB期霍奇金淋巴瘤，引起了严重的生命威胁性中性粒细胞减少症。通过在化疗给药期间中断洛匹那韦-利托那韦来管理长春碱和洛匹那韦-利托那韦的相互作用，六周期后实现了完全缓解和免疫病毒学成功。

A HIV infected patient was treated for stage IVB Hodgkin's lymphoma by ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy and lopinavir-ritonavir based antiretroviral therapy inducing profound life-threatening neutropenia. Vinblastine and lopinavir-ritonavir interaction was managed with lopinavir-ritonavir interruption around chemotherapy administration, with complete remission and immunovirological success after six cycles.

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、癫痫、低血压和心律失常，请予以治疗。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，并通过注射器负压尽可能多地抽取液体。然后给予以下特定治疗：在区域上放置加热垫，并在24小时内间歇性加热；抬高患肢。局部注射透明质酸酶可能有益。不要使用冰袋。/如果条件适当，口服活性炭进行解毒。在小到中等摄入量后，如果可以迅速给予活性炭，则不需要进行胃灌洗。由于这些药物迅速进入细胞内，透析和其他体外去除程序通常效果不佳。/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 beneficial. Do not use ice packs. /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸长春碱从胃肠道吸收不可预测。静脉给药后，药物会迅速从血液中清除并分布到身体组织中。硫酸长春碱很难穿过血脑屏障，并且在治疗浓度下不会出现在脑脊液中。

Vinblastine sulfate is unpredictably absorbed from the GI tract. Following iv administration, the drug is rapidly cleared from the blood and distributed into body tissues. Vinblastine crosses the blood brain barrier poorly and does not appear in the CSF in therapeutic concentrations.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

中央室的体积占体重的70%，这很可能反映了组织与血液有形成分的非常快速的结合。发生广泛的可逆组织结合。在注射后48小时和72小时，体内存储量较低。

The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs. Low body stores are present at 48 and 72 hours after injection.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在向人类癌症患者注射放射性同位素标记的长春碱后，发现10%的放射性活性出现在粪便中，14%出现在尿液中；剩余的活动性未作说明。在狗身上的类似研究表明，在9天内，30%至36%的放射性活性出现在胆汁中，12%至17%出现在尿液中。在大鼠身上的类似研究发现，注射后2小时，放射性活性的最高浓度出现在肺、肝、脾和肾中。

Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the feces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over 9 days, 30% to 36% of radioactivity was found in the bile and 12% to 17% in the urine. A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen, and kidney 2 hours after injection.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

目前尚不清楚这种药物是否会被分泌入人乳中。

It is not known whether this drug is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品运输编号：
  UN 1544
• 包装等级：
  II
• 危险类别：
  6.1(a)

制备方法与用途

长春碱是从长春花中提取的药物，具有抗癌作用，广泛应用于临床抗肿瘤治疗，具有很高的药用价值。

化学性质 长春碱为白色结晶体，可溶于甲醇、乙醇和DMSO等有机溶剂，来源于长春花。

用途 主要用于治疗恶性淋巴瘤。