Vinorelbine Ditartarate | 71486-22-1

• 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: Vinorelbine Ditartarate
• 英文别名: methyl (1R,9R,10R,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(12S,14R)-16-ethyl-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8,15-pentaen-12-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: 71486-22-1
• 化学式: C₄₅H₅₄N₄O₈
• 分子量: 778.9
• InChiKey: GBABOYUKABKIAF-GHYRFKGUSA-N

物化性质

• 比旋光度：
  D20 +52.4° (c = 0.3 in CHCl3)
• 密度：
  1.36±0.1 g/cm3(Predicted)
• 溶解度：
  >25.9mg/mL，溶于 DMSO
• 物理描述：
  Solid
• 稳定性/保质期：

  Unopened vials of vinorelbine tartrate injection are stable at temperatures up to 25 °C for up to 72 hours. Vinorelbine tartrate injection should not be frozen.

• 旋光度：
  Specific optical rotation: +52.4 deg at 20 °C/D ( c = 0.3 in CHCl3)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  57
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

代谢

长春瑞滨在肝脏中被广泛代谢。长春花碱类（例如，长春碱、长春新碱）的代谢是通过细胞色素P-450（CYP）同工酶中的CYP3A亚家族介导的。长春瑞滨的两个代谢物，长春瑞滨N-氧化物和去乙酰长春瑞滨，已在人类血液、血浆和尿液中被发现。

Vinorelbine is extensively metabolized in the liver. The metabolism of vinca alkaloids (eg, vinblastine, vincristine) is mediated by the cytochrome P-450 (CYP) isoenzymes in the CYP3A subfamily. Two metabolites of vinorelbine, vinorelbine N-oxide and deacetylvinorelbine, have been identified in human blood, plasma, and urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

去乙酰长春瑞滨，是人类长春瑞滨的主要代谢物，已经显示出与母药相似的抗肿瘤活性。然而，长春瑞滨的治疗剂量导致血液或尿液中这两种代谢物的浓度非常小，几乎无法量化。

Deacetylvinorelbine, the primary metabolite of vinorelbine in humans, has been shown to possess antitumor activity similar to the parent drug. However, therapeutic doses of vinorelbine result in very small, if any, quantifiable concentrations of either metabolite in blood or urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

关于长春瑞滨的生物转化知之甚少。脱乙酰长春瑞滨被认为是一种次要代谢物，仅存在于尿液组分中，占注射剂量的0.25%。

... Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

脱乙酰化产生脱乙酰纳avelbine（DNVB）是长春瑞滨（纳avelbine，NVB）的主要代谢途径。这种细胞毒代谢物占药物整体处置的很大一部分。只有58%的给药剂量以NVB或DNVB的形式从尿（17%）和粪便（41%）中排出。没有检测到其他代谢物。

... Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for vinorelbine (navelbine, NVB). This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and feces (41%) as NVB or DNVB. No other metabolites have been detected.

来源:Hazardous Substances Data Bank (HSDB)

代谢

长春瑞滨在与大鼠肝微粒体孵化后产生了一个主要代谢物（M1）。在大鼠静脉给药后的胆汁和粪便中，通过高效液相色谱（HPLC）鉴定出了除M1以外的几个主要代谢物。通过比较HPLC保留时间和对二维核磁共振（NMR）以及混合质谱/质谱（MS/MS）光谱的广泛分析，确定这些主要代谢物的结构为15,16-环氧长春瑞滨（M1）、11'-羟基长春瑞滨（M2）、19'-羟基长春瑞滨（M3a）、15,16-环氧-10'-羟基长春瑞滨（M3b）和10'-羟基长春瑞滨（M4）。

Vinorelbine produced a dominant metabolite (M1) after incubation with rat liver microsomes. Several major metabolites other than M1 were identified by HPLC in bile and feces of rat after intravenous administration. The structures of the major metabolites were identified as 15,16-epoxyvinorelbine (M1), 11'-hydroxyvinorelbine (M2), 19'-hydroxyvinorelbine (M3a), 15,16-epoxy-10'-hydroxyvinorelbine (M3b) and 10'-hydroxyvinorelbine (M4) by comparison of HPLC retention times and by extensive analyses of two-dimensional NMR and hybrid MS/MS spectra.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

长春瑞滨和紫杉醇的联合给药可能与神经病变风险增加有关。

Concomitant administration of vinorelbine and paclitaxel may be associated with an increased risk of neuropathy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在同时使用长春花碱和抗呕吐药阿瑞吡坦期间，建议谨慎并密切监测，因为阿瑞吡坦可能会抑制或诱导CYP3A4。

Caution and careful monitoring are advised during concomitant use of a vinca alkaloid and aprepitant, an antiemetic agent, which may inhibit or induce CYP3A4.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

因为据报道，接受长春花碱类药物的患者出现了前庭缺陷以及与第八对脑神经损伤相关的不同程度的永久性或暂时性听力损害，所以在与其他可能具有耳毒性的药物，如含有铂类的抗肿瘤药物同时使用时，应极度谨慎。

Because vestibular deficits and varying degrees of permanent or temporary hearing impairment associated with damage of the eighth cranial nerve have been reported in patients receiving vinca alkaloids, vinorelbine should be used concomitantly with other potentially ototoxic drugs, such as platinum-containing antineoplastic agents, with extreme caution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一位41岁的女性在就诊前三年接受了左侧乳房切除术治疗乳腺癌。六个月前，她出现了复发，这次是在右侧乳房和皮肤。尽管进行了第一线和第二线的化疗，肿块仍显示出疾病进展。此后，她开始接受每周一次的长春瑞滨和曲妥珠单抗治疗，但一个月后，她出现了轻微发热和干咳。胸部CT扫描显示右肺有一个浸润阴影，呈现非特异性的间质模式。支气管镜检查显示支气管灌洗液中淋巴细胞占优势，通过经支气管肺活检在组织标本中发现淋巴细胞浸润到间质并伴有纤维化。在停止上述长春瑞滨治疗后，患者的病情有所改善。因此，研究者们诊断这是一例长春瑞滨和曲妥珠单抗引起的间质性肺炎。

A 41-year-old woman had undergone a left mastectomy breast cancer three years prior to presentation. Six months /ago/ she had recurrence, this time in the right breast and skin. Despite first-and second-line chemotherapy, the mass showed progression of the disease. Thereafter, a weekly treatment of vinorelbine and trastuzumab was started, but one month later, she developed a slight fever and dry cough. A chest CT scan revealed an infiltration shadow showing non-specific interstitial pattern in the right lung. A bronchoscopic examination showed lymphocyte dominance in bronchial lavage fluid, and lymphocyte infiltration into the interstium with fibrosis in the tissue specimens was found by transbronchial lung biopsy. After discontinuing the above vinorelbine therapy, the patient's condition improved. /Investigators/ therefore diagnosed this as a case of vinorelbine-and trastuzumab-induced interstitial pneumonia.

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。/对于/去污，如果条件合适，口服活性炭。如果可以及时给予活性炭，则在少量到中等摄入后不需要进行胃灌洗。由于这些药物的快速细胞内结合，透析和其他体外清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

静脉给药后，血浆长春瑞滨浓度最初迅速下降，代表药物向周边室分布。在给予30毫克/平方米的长春瑞滨静脉注射，持续15-20分钟后，已报道稳态分布容积为25.4-40.1升/公斤。

The initial rapid decline in plasma vinorelbine concentration following iv administration represents distribution of the drug to peripheral compartments. Following administration of vinorelbine 30 mg/sq m iv over 15-20 minutes, a steady-state volume of distribution of 25.4-40.1 L/kg has been reported.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

长春瑞滨与人体血小板和淋巴细胞的结合力较高。在癌症患者中，药物与血浆成分的结合率在79.6-91.2%之间，并且在混合人血浆中，观察到大约0.11的自由分数，浓度范围为234-1169 ng/mL。顺铂、氟尿嘧啶或多柔比星的存在并不影响长春瑞滨的结合。

Vinorelbine demonstrates high binding to human platelets and lymphocytes. Binding of the drug to plasma constituents in patients with cancer ranges from 79.6-91.2%, and a free fraction of approximately 0.11 was observed in pooled human plasma over a concentration range of 234-1169 ng/mL. The presence of cisplatin, fluorouracil, or doxorubicin does not affect vinorelbine binding.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射放射性标记的长春瑞滨后，大约46%的给药剂量在粪便中回收，18%在尿液中。在另一项研究中，大约11%的静脉给药剂量长春瑞滨以原形在尿液中排泄。

Following IV administration of radiolabeled vinorelbine, approximately 46% of the administered dose was recovered in the feces and 18% in the urine. In another study, approximately 11% of an administered IV dose of vinorelbine was excreted unchanged in the urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

食物对软胶囊制剂长春瑞滨（口服长春瑞滨）的药代动力学和安全性的影响在实体瘤或淋巴瘤的禁食和进食患者中进行了评估。一组18名患者（计划12名）被纳入了一个多中心I期药代动力学研究，该研究采用交叉设计，有1周的清洗期。患者在禁食或摄入标准的大陆早餐后接受了第一个80 mg/平方米口服长春瑞滨的剂量。一周后，在第一次给药的相反饮食条件下，给予第二个80 mg/平方米的剂量。在18名患者中，有13名符合药代动力学评估的条件。禁食患者的平均达峰时间（Tmax）较短（血液中为1.63±0.98小时，血浆中为1.67±0.96小时），而进食患者的平均达峰时间较长（血液中为2.48±1.40小时，血浆中为2.56±1.65小时），但这些差异不太可能改变口服长春瑞滨的安全性和/或有效性。进食和禁食患者的Cmax和AUC值相似，没有观察到显著差异。在这有限数量的患者中观察到的口服长春瑞滨的安全性与通常报告的长春瑞滨的安全性相似，主要毒性是中性粒细胞减少。只报告了一次发热性中性粒细胞减少的发作。遇到的主要非血液学毒性是胃肠道毒性，包括恶心、呕吐、腹泻和便秘。当口服长春瑞滨在标准早餐后给药时，呕吐的发生率似乎有降低的趋势。根据这项研究，口服长春瑞滨给药于禁食患者不是强制性的，因为在标准早餐后给药不会导致药物在体内的暴露差异。

The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicenter phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/sq m oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/sq m was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (T(max)) was shorter in fasted patients (1.63+/-0.98 hr in blood, 1.67+/-0.96 hr in plasma) than in fed patients (2.48+/-1.40 hr in blood, 2.56+/-1.65 hr in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for C(max) and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. ...

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

功效与作用

长春瑞宾（Navelbine）是Pierre Fabre公司在20世纪90年代中期开发的一种新型长春花碱类药物。它是一种半合成衍生物，由长春花属植物中的化合物衍生而来，主要通过抑制细胞有丝分裂，在有丝分裂中期对细胞活动进行阻断。长春瑞宾与微管蛋白单体结合，阻碍微管形成。如果没有足够的微管，新复制的染色体会无法被拉开，导致细胞分裂受阻并诱导细胞凋亡。该药物具有高度脂溶性，能够完全解聚微管。

可治疗的恶性肿瘤

长春瑞宾适用于以下几种癌症：

• 乳腺癌
• 睾丸癌
• 卵巢上皮细胞癌
• 非小细胞肺癌

用法用量

给药方法一般为25～30mg/m²，静脉滴注，每周1次，连续4～6次为一个疗程。最新研究显示，每2～3周给予一次50mg/m²的剂量也能被多数患者耐受。

不良反应

常见不良反应包括：

• 骨髓抑制：导致血小板、红细胞及白细胞减少和贫血，大部分在7天内恢复。
• 神经毒性：表现为腱反射减低、便秘或腹泻，罕见麻痹性肠梗阻。此外还有手足麻木、气短、恶心、呕吐和脱发。

注意事项

1. 由于此药可能导致出生缺陷，妊娠或准备妊娠的妇女不应使用该药物。正在使用的患者不宜哺乳。
2. 正在接受该药物治疗的患者不应进行预防接种，因为这会因白细胞减少导致免疫力下降而增加感染风险。同时应避免与刚口服过“脊灰”疫苗的人接触。
3. 药物对静脉有刺激性，注射完毕后应再给予100～250ml生理盐水冲洗静脉，以防止外渗。
4. 用药时避免药物沾染眼球，以免造成角膜溃疡。
5. 使用前需用生理盐水或5%葡萄糖注射液稀释，并在密封玻璃瓶中于室温下保存24小时。

化学性质

• [α]D₂₀+52.4° (C=0.3，氯仿)
• UV最大吸收：乙醇中为215、268、282、293、310nm（ε 3700、11000、9500、7600、4400）
• 二酒石酸长春瑞滨 (Vinordbine Ditartrate): C₄₅H₅₄N₄O_{8·2C4H6O6>，黄白色无定形粉末。溶于水或乙醇。}

用途

• 半合成长春花生物碱，具有广谱抗肿瘤活性且毒性较低。
• 干扰细胞有丝分裂期微管的聚集而产生细胞毒作用。
• 主要用于非小细胞肺癌、乳腺癌、卵巢癌、软组织及内脏转移癌和淋巴癌。

药理药效

主要通过与微管蛋白结合，干扰细胞在有丝分裂过程中微管的形成。

生产方法

长春瑞宾由脱水长春碱（Anhydmvinblastine）经过1步或2步反应得到。