依托泊苷 | 33419-42-0

• 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 - 木脂素、新木脂素和相关化合物 - 木脂素内酯
• 中文名称: 依托泊苷
• 中文别名: 依托泊甘；4'-去甲基表鬼臼毒素-beta-D-乙叉吡喃葡萄糖甙；依托泊甙；足叶乙甙；鬼臼亚乙基苷；4"-去甲基表鬼臼毒素-beta-D-乙叉吡喃葡萄糖甙；足叶乙苷；表鬼臼毒吡喃葡萄糖苷
• 英文名称: etoposide
• 英文别名: VP 16；ETO；(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one
• CAS: 33419-42-0
• 化学式: C₂₉H₃₂O₁₃
• mdl: MFCD00869325
• 分子量: 588.565
• InChiKey: VJJPUSNTGOMMGY-MRVIYFEKSA-N

物化性质

• 熔点：
  236-251 °C (lit.)
• 比旋光度：
  D20 -110.5° (c = 0.6 in chloroform)
• 沸点：
  563.9°C (rough estimate)
• 密度：
  1.2966 (rough estimate)
• 溶解度：
  在DMSO中的溶解度为30 毫克/毫升
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from methanol
• 蒸汽压力：
  5.4X10-23 mm Hg at 25 °C /Estimated/
• 旋光度：
  Specific optical rotation = -110.5 °C @ 20 °C/D ( c= 0.6 in chloroform).
• 解离常数：
  pKa = 9.8
• LogP：
  0.6

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  42
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.551
• 拓扑面积：
  161
• 氢给体数：
  3
• 氢受体数：
  13

ADMET

代谢

主要通过肝脏（通过CYP450 3A4同工酶途径的O-脱甲基化）代谢，40%以原型药物形式从尿液中排出。依托泊苷还经历谷胱甘肽和葡萄糖醛酸结合，分别由GSTT1/GSTP1和UGT1A1催化。前列腺素合酶也负责将依托泊苷转化为O-脱甲基化代谢物（醌）。

Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively. Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone).

来源:DrugBank

代谢

提议的依托泊苷的羟基酸代谢物，通过开环乳内酯环形成，已经在人类尿液中检测到，但浓度较低，仅占给药剂量的0.2-2.2%。

The proposed hydroxy acid metabolite of etoposide, formed by opening of the lactone ring, has been detected in human urine, but only at low concentrations, accounting for 0.2-2.2% of the administered dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

依托泊苷是人类的主要尿液代谢物，据报道是葡萄糖苷酸结合物。尽管报告称尿液中的葡萄糖苷酸和/或硫酸盐结合物占静脉注射依托泊苷剂量的5-22%，但其他研究表明葡萄糖苷酸占主导地位。接受治疗的患者的尿液中依托泊苷葡萄糖苷酸占0.5-3.5 g/平方米剂量的8-17%，在100-800 mg/平方米剂量的依托泊苷中占29%，在后一项研究中除了依托泊苷葡萄糖苷酸外没有检测到其他代谢物。在给予70-150 mg/平方米较低剂量的肾或肝功能受损患者中，3-17%的剂量在72小时内以依托泊苷葡萄糖苷酸的形式从尿液中排出。

The major urinary metabolite of etoposide in humans is reported to be the glucuronide conjugate. Although urinary glucuronide and/or sulfate conjugates were reported to account for 5-22% of an intravenous dose of etoposide, other studies suggest that the glucuronide predominates. Etoposide glucuronide in the urine of treated patients accounted for 8-17% of a dose of 0.5-3.5 g/sq m etoposide and 29% of a dose of 100-800 mg/sq m etoposide, with no other metabolites other than etoposide glucuronide detected in the latter study. In patients with renal or liver impairment given somewhat lower doses of 70-150 mg/sq m, 3-17% of the dose was excreted in the urine within 72 hr as etoposide glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

依托泊苷似乎主要在D环代谢，产生相应的羟基酸（可能是反式羟基酸）；这种代谢物在药理上似乎是无效的。一些患者的血浆和尿液中检测到了依托泊苷的吡咯内酯异构体，但其他患者中并未检测到。迄今为止，在接受依托泊苷药物治疗的患者中尚未检测到依托泊苷的苷元及其缀合物。在体外实验中，依托泊苷的吡咯内酯异构体和苷元具有最小的细胞毒性活性。

Etoposide appears to be metabolized principally at the D ring to produce the resulting hydroxy acid (probably the trans-hydroxy acid); this metabolite appears to be pharmacologically inactive. The picrolactone isomer of etoposide has been detected in two concentrations in the plasma and urine of some patients but not in others. The aglycone of etoposide and/or its conjugates have not been detected to date in patients receiving the drug. In vitro, the picrolactone isomer and aglycone of etoposide have minimal cytotoxic activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

通常情况下，在血浆中很少或没有检测到依托泊苷的代谢物。依托泊苷作为反式-内酯形式给药，但在人尿液中也可以检测到顺式-依托泊苷。这可能是储存现象，因为在稍微偏碱性的条件下冷冻血浆样本时，有时会发生异构化。顺式异构体占剂量小于1%。在接受600 mg/平方米依托泊苷的患者中，还报告了儿茶酚代谢物，其曲线下面积（AUC）约为依托泊苷的2.5%。在接受90 mg/平方米依托泊苷的患者中，儿茶酚代谢物占尿液中依托泊苷的1.4-7.1%，占给药剂量的小于2%。

Generally, few or no etoposide metabolites have been detected in plasma. Etoposide is administered as the trans-lactone, but cis-etoposide can also be detected in human urine. This might be a storage phenomenon, since isomerization sometimes occurs during freezing of plasma samples under slightly basic conditions. The cis isomer accounts for < 1% of the dose. The catechol metabolite has also been reported in patients receiving 600 mg/sq m etoposide, with an AUC of around 2.5% that of etoposide. In patients given 90 mg/sq m etoposide, the catechol metabolite represented 1.4-7.1% of the urinary etoposide and < 2% of the administered dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

依托泊苷抑制DNA拓扑异构酶II，从而抑制DNA的再连接。这会导致细胞分裂前期的DNA合成中出现关键错误，并可能导致癌细胞凋亡。依托泊苷对细胞周期依赖且对特定阶段敏感，主要影响细胞分裂的S期和G2期。抑制拓扑异构酶II的α亚型产生依托泊苷的抗肿瘤活性。该药物也能抑制β亚型，但抑制这个靶点与抗肿瘤活性无关，而是与致癌作用相关。

Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：依托泊苷

Compound:etoposide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

吸收良好，达到血浆峰浓度的时间为1-1.5小时。平均生物利用度为50%（范围在25% - 75%之间）。口服依托泊苷胶囊的Cmax和AUC值表现出受试者内和受试者间的变异性。没有证据显示依托泊苷有首过效应。

Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide.

来源:DrugBank

吸收、分配和排泄

• 消除途径

依托泊苷通过肾脏和非肾脏过程清除，即代谢和胆汁排泄。依托泊苷的葡萄糖醛酸苷和/或硫酸盐结合物也通过尿液排出。未改变的药物和/或代谢物的胆汁排泄是依托泊苷消除的重要途径，因为放射性物质通过粪便回收的比例是静脉注射剂量的44%。剂量的56%出现在尿液中，其中45%以依托泊苷形式排出。

Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. 56% of the dose was in the urine, 45% of which was excreted as etoposide.

来源:DrugBank

吸收、分配和排泄

• 分布容积

依托泊苷的处置是一个双相过程，分布半衰期为1.5小时。它不易穿过进入脑脊液。稳态体积分布为18 - 29升。

The disposition of etoposide is a biphasic process with a distribution half-life of 1.5 hours. It does not cross into cerebrospinal fluid well. Volume of distribution, steady state = 18 - 29 L.

来源:DrugBank

吸收、分配和排泄

• 清除

总体清除率 = 33 - 48 mL/min [静脉给药，成人]

Total body clearance = 33 - 48 mL/min [IV administration, adults]

来源:DrugBank

吸收、分配和排泄

依托泊苷在一位接受每日80毫克/平方米剂量（给药途径未说明）的急性早幼粒细胞白血病妇女的乳汁中排出得到证实。给药后立即测得的峰值浓度为0.6至0.8微克/毫升，但24小时后已降至检测不到的水平。

Excretion of etoposide in breast milk was demonstrated in a woman with acute promyelocytic leukemia receiving daily doses of 80 mg/sq m (route not stated). Peak concentrations of 0.6 to 0.8 ug/mL were measured immediately after dosing but had decreased to undetectable levels by 24 hr.

来源:Hazardous Substances Data Bank (HSDB)