(8aR,9R)-5-[[(4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-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

• 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
• 英文名称: (8aR,9R)-5-[[(4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-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
• 英文别名: (5S,5aR,8aR,9R)-5-[[(4aR,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-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
• 化学式: C₃₂H₃₂O₁₃S
• 分子量: 656.7
• InChiKey: NRUKOCRGYNPUPR-ZVYBSHBNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  46
• 可旋转键数：
  6
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  189
• 氢给体数：
  3
• 氢受体数：
  14

ADMET

代谢

在人离体肝脏制剂中，细胞色素P450混合功能同工酶催化了（悬挂）E环的代谢，生成了O-去甲基化和儿茶酚代谢物。这种代谢主要归因于CYP3A4的活性，其次是由于CYP3A5。还报道了过氧化物酶介导的替尼泊苷的O-去甲基化。

In isolated human liver preparations, cytochrome P450 mixed-function isozymes catalysed metabolism of the (pendant) E-ring to O-demethylated and catechol metabolites. This metabolism was subsequently attributed primarily to CYP3A4 activity and to a lesser degree to CYP3A5. Peroxidase-mediated O-demethylation of teniposide has also been reported.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予替尼泊苷的儿童中，血清和尿液中报告的主要代谢物是羟基酸，由内酯环的开环形成；还检测到了顺式异构体，可能是储存过程中形成的降解产物。没有检测到由葡萄糖苷部分丢失形成的苷元（Evans等人，1982年）。在其他使用高剂量替尼泊苷的研究中，血浆或尿液中没有发现羟基酸，并且在与葡萄糖苷酸酶孵育后，这些样品中替尼泊苷的测量浓度没有变化，这表明形成的拟议的葡萄糖苷酸代谢物很少或没有（Holthuis等人，1987年）。然而，在另一项研究中，给予的替尼泊苷剂量的6%在24小时内以母药形式排出尿液，另外8%以拟议的苷元葡萄糖苷酸形式排出，后者没有正式鉴定。

In children given teniposide, the main metabolite in serum and urine was reported to be the hydroxy acid, formed by opening of the lactone ring; the cis-isomer, which may be a degradation product formed during storage, was also detected. The aglycone, formed by loss of the glucopyranoside moiety, was not detected (Evans et al., 1982). The hydroxy acid has not been found in plasma or urine in other studies with high doses of teniposide, and no changes in the measured concentration of teniposide in these samples was found after incubation with glucuronidase, indicating formation of little or none of the proposed glucuronide metabolites (Holthuis et al., 1987). In another study, however, 6% of the administered dose of teniposide was excreted in the urine as parent drug over 24 h, and a further 8% as a proposed aglycone glucuronide, which was not formally identified.

来源:Hazardous Substances Data Bank (HSDB)

代谢

通常情况下，在哺乳动物体外细胞中，替尼泊苷的作用并不需要外源性代谢激活。已经鉴定出了替尼泊苷的各种代谢产物，但它们的致突变性质尚未进行研究。

In general, the effects of teniposide in mammalian cells in vitro occurred in the absence of exogenous metabolic activation. Various metabolic species of teniposide have been identified, but their mutagenic properties have not been studied.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

使用依托泊苷或替尼泊苷与其他药物联合化疗与5%至超过50%的患者血清酶升高有关，具体取决于剂量和其他使用的药物。ALT升高通常是无症状的和短暂的，可能会在没有剂量调整的情况下解决。在许多情况下，由于暴露于其他可能具有肝毒性的药物，很难将肝功能测试异常归因于依托泊苷或替尼泊苷。已经报道了在接受依托泊苷治疗的患者中出现临床明显的肝损伤的罕见实例，但是损伤发生的时间和模式有很大的差异。发病时间可以从治疗开始后短至1个月到长达5个月。一些发表的病例在包括依托泊苷的化疗方案后出现肝损伤，似乎代表门脉阻塞性综合征。这些病例通常在依托泊苷治疗联合使用烷化剂或全身照射后出现。此外，依托泊苷还与治疗1至5个月后发生的急性肝炎病例有关，这些病例通常是自限性的，但偶尔也会很严重。依托泊苷在引起损伤中的作用并不总是明确的。报告的病例中血清酶升高的模式是肝细胞型的。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）和自身抗体缺失。依托泊苷肝毒性的肝脏组织学尚未得到很好的描述。替尼泊苷的肝毒性定义不如依托泊苷明确，这可能是由于它的使用有限。 可能性评分，依托泊苷：C（可能是临床明显肝损伤的原因）。 可能性评分，替尼泊苷：E*（未证实但疑似是临床明显肝损伤的原因）。

Chemotherapy with etoposide or teniposide in combination with other agents is associated with serum enzyme elevations in 5% to more than 50% of patients, depending upon the dose and other agents used. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to etoposide or teniposide because of the exposure to other potentially hepatotoxic agents. Rare instances of clinically apparent liver injury have been reported in patients receiving etoposide, but the time to onset and pattern of injury has varied greatly. Onset can be as short as 1 to as long as 5 months after initiation of therapy. Some published cases of liver injury after regimens of chemotherapy that have included etoposide appear to represent sinusoidal obstruction syndrome. These cases have usually followed etoposide therapy in combination with an alkylating agent or total body irradiation. In addition, etoposide has been linked to cases of acute hepatitis arising after 1 to 5 months of treatment, which have generally been self-limiting, but occasionally severe. The role of etoposide in causing injury was not always clear. The pattern of serum enzyme elevation in reported cases has been hepatocellular. Immunoallergic features (rash, fever, eosinophilia) and autoantibodies were absent. The liver histology of etoposide hepatotoxicity has not been well characterized. The hepatotoxicity of teniposide has been less well defined than that of etoposide, probably because it has had limited use. Likelihood score, etoposide: C (probable cause of clinically apparent liver injury). Likelihood score, teniposide: E* (unproven but suspected cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 致癌性证据

评估：对于替尼泊苷在人类中的致癌性，证据有限。对于依托泊苷在实验动物中的致癌性，证据不足。总体评估：替尼泊苷可能对人类具有致癌性（2A组）。在得出这一评估时，工作组注意到依托泊苷能在白血病细胞中引起独特的细胞遗传学损伤，这些损伤可以轻易地与由烷化剂诱导的损伤区分开来。这些白血病的短暂潜伏期与由烷化剂诱导的白血病相比有所不同。在体外的人细胞和体内动物细胞中，会发生强烈的蛋白遮蔽DNA断裂和致裂效应。

Evaluation: There is limited evidence in humans for the carcinogenicity of teniposide. There is inadequate evidence in experimental animals for the carcinogenicity of etoposide. Overall evaluation: Teniposide is probably carcinogenic to humans (Group 2A). In reaching this evaluation, the Working Group noted that etoposide causes distinctive cytogenetic lesions in leukemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukemias contrasts with that of leukemia induced by alkylating agents. Potent protein masked DNA breakage and clastogenic effects occur in human cells in vitro and animal cells in vivo.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

环孢素以5 mg/kg bw的剂量在2小时内给药，随后以30 mg/kg bw的剂量在48小时内静脉给药，使替尼泊苷的曲线下面积（AUC）增加了50%，这是由于清除率降低所致。相反，同时给予苯妥英钠，使替尼泊苷的清除率从对照患者的13 mL/min/平方米增加到32 mL/min/平方米。

Concurrent administration of ciclosporin at 5 mg/kg bw over 2 h, followed by 30 mg/kg bw over 48 h intravenously, increased the AUC for teniposide by 50%, due to a reduction in clearance. Conversely, concurrent administration of phenytoin increased the clearance rate of teniposide to 32 mL/min per m2 from 13 mL/min per m2 for control patients.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

过量处理：建议根据情况给予支持性血液产品和抗生素治疗。目前没有已知的解毒剂。

Treatment of overdose: Supportive blood product and antibiotic therapy, as indicated, is recommended. There is no known antidote.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施；1. 保持呼吸道通畅，必要时协助通气。2. 如出现昏迷、惊厥、低血压和心律失常，应予以治疗。3. 使用甲氧氯普胺治疗恶心和呕吐，以及使用静脉晶体液治疗由胃肠炎引起的液体丢失。4. 骨髓抑制应在经验丰富的血液学家或肿瘤学家的帮助下治疗。5. 渗漏。立即停止输液，并通过注射器的负压尽可能多地抽回液体。然后给予以下特定治疗。... 在该区域放置加热垫，并在24小时内间歇性地加热；抬高肢体。局部注射透明质酸酶... 可能有益。不要使用冰袋。/抗肿瘤药物/。

Emergency and supportive measures; 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, and arrhythmias if they occur.3. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. 4. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. 5. 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 pack. /Antineoplastic Agents/.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

替尼泊苷在11名接受100-150 mg/平方米替尼泊苷治疗的患者的大脑内肿瘤中的浓度在0.05-1.12微克/克组织之间，这些患者在肿瘤切除前1.5-3小时接受了治疗。在3名患者中，邻近的正常脑组织中的浓度较低（小于0.9微克/克组织），而在其他患者中则检测不到（小于0.05微克/克组织）。

Teniposide was detected in intracerebral tumors at concentrations of 0.05-1.12 ug/g tissue in 11 patients given 100-150 mg/sq m teniposide 1.5-3 hr before tumor resection. The concentrations in adjacent normal brain tissue were low (< 0.9 ug/g tissue) in three patients and undetectable (< 0.05 ug/g tissue) in the others

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

替尼泊苷在一个患者体内被检测到，该患者在累计静脉给药576毫克后三天死亡，最高浓度出现在脾脏、前列腺、心脏、大肠、肝脏和胰腺。

Teniposide was detected in one patient who died three days after a cumulative intravenous dose of 576 mg, the highest concentrations occurring in the spleen, prostate, heart, large bowel, liver and pancreas.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

替尼泊苷是否分布进入乳汁尚不清楚。

It is not known whether teniposide is distributed into breast milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：肾脏：4%至12%的剂量以未改变的依托泊苷形式排出。在一项对成年人进行的氚标记依托泊苷研究中，给药后120小时内，尿液中有44%的放射性标记（母化合物和代谢物）被回收。粪便：0%至10%的剂量。

Elimination: Renal: 4 to 12% of a dose as unchanged teniposide. In a study of tritium-labeled teniposide in adults, 44% of the radiolabel (parent compound and metabolites) was recovered in urine within 120 hours after dosing. Fecal: 0 to 10% of a dose.

来源:Hazardous Substances Data Bank (HSDB)