Leurocristine;NSC-67574;22-Oxovincaleukoblastine

• 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: Leurocristine;NSC-67574;22-Oxovincaleukoblastine
• 英文别名: methyl (1R,10S,12R)-11-acetyloxy-12-ethyl-4-[(13S,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
• 化学式: C₄₆H₅₆N₄O₁₀
• 分子量: 825.0
• InChiKey: OGWKCGZFUXNPDA-BWGBWKQMSA-N

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，可能在肝脏中，但代谢程度不清楚，因为该药物在体内显然也会发生分解。

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）同时给药已被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的联合给药已被报道会降低抗惊厥药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液水平监测。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消除速率增加所导致。

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的总神经突起长度来量化。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

长春新碱已显示出能够克服P388白血病对长春碱的获得性耐药性，无论是在体外还是体内。为了研究这种作用的特异性，研究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长春新碱对长春碱细胞毒性的影响。使用差染细胞毒性分析，证明了1 uM浓度的长春新碱在0.04-0.25 ug/L的浓度下增强了长春碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性。然而，对抗对照组的外周血淋巴细胞并未观察到细胞毒性的增强。数据显示长春新碱优先增强长春碱对慢性淋巴细胞白血病和GM 3639细胞的体外细胞毒性，但并未观察到对外周血淋巴细胞细胞毒性的增强。

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、癫痫、低血压和心律失常，应予以治疗。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，间歇性加热24小时；抬高患肢。局部注射透明质酸酶可能有益。不要使用冰袋。/对于/去污，如果条件合适，口服活性炭。在小到中等量摄入后，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，透析和其他体外去除程序通常无效。/抗癌药物/

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

中枢神经系统白血病在接受长春新碱治疗并处于血液学缓解期的患者中的发展被解释为证据表明...长春新碱...穿透血脑屏障的能力较差。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，局部摄取或破坏非常迅速。长春花生物碱似乎主要通过肝脏排入胆汁。

Development of CNS leukemia in patients receiving vincristine and in hematological remission has been interpreted as evidence that ... /vincristine/ penetrates blood-brain barrier poorly. Vincristine ... can be infused into arterial blood supply of tumors in doses several times larger than those that can be admistered iv with comparable toxicity; thus either local uptake or destruction is very rapid. Vinca alkaloids appear to be excreted primarily by liver into bile.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

注射后的头几个小时内，狗和猴子尿液排泄量较低。在两者中，药物分布到大多数组织中，但浓度最高的部位是肺、肾、脾、胰腺和肝脏。在猴子中，长春新碱及其代谢物迅速从血浆进入脑脊液，形成低浓度的药物，这种状态持续了数天。

Urinary excretion ... over first few hr after injection was ... low in dogs and monkeys. In both ... the drug was distributed to most tissues, but highest concentrations ... found in lung, kidney, spleen, pancreas and liver. In monkeys, vincristine and its metabolites rapidly entered cerebrospinal fluid from plasma to form low concentrations of drug, which persisted for several days.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

硫酸长春新碱从胃肠道的吸收是不可预测的。在肾功能和肝功能正常的患者中，快速静脉注射2毫克剂量的长春新碱后，血药浓度会立即达到大约0.19-0.89微摩尔/升的峰值，并且药物会迅速从血液中清除。与快速静脉注射相同剂量药物相比，持续静脉输注时血清长春新碱浓度-时间曲线下的面积有所增加。

Vincristine sulfate is unpredictably absorbed from the Gl tract. Following rapid iv injection of a 2 mg dose of vincristine in patients with normal renal and hepatic function, peak serum drug concentrations of approximately 0.19-0.89 uM occur immediately and the drug is rapidly cleared from serum. The area under the serum vincristine concentration time curve has been shown to be increased following continuous iv infusion compared with rapid iv injection of the drug when comparable doses are administered.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

长春新碱及其代谢物（和/或分解产物）在人体组织和体液中的分布尚未被完全表征，但药物在静脉给药后迅速且广泛分布。分布到组织中的药物紧密结合但可逆。长春新碱及其代谢物（和/或分解产物）迅速且广泛地分布到胆汁中，在快速静脉注射药物后2-4小时内胆汁中达到峰值浓度。长春新碱及其代谢物（和/或分解产物）在快速静脉注射后很少穿过血脑屏障，通常不会在脑脊液中以细胞毒浓度出现。

Distribution of vincristine and its metabolites (and/or decomposition products) into human body tissues and fluids has not been fully characterized, but the drug is rapidly and apparently widely distributed following iv administration. Drug that is distributed into tissues is tightly but reversibly bound. Vincristine and its metabolites (and/or decomposition products) are rapidly and extensively distributed into bile, with peak biliary concentrations occurring within 2-4 hr after rapid iv injection of the drug. Vincristine and its metabolites (and/or decomposition products) cross the blood brain barrier poorly following rapid iv injection and generally do not appear in the CSF in cytotoxic concentrations.

来源:Hazardous Substances Data Bank (HSDB)