imatinib mesylate | 220127-57-1

• 物质功能分类: 原料药 - 抗肿瘤药 - 替尼类抗肿瘤药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: imatinib mesylate
• 英文别名: gleevec；STI571；4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate；imatinib；Glivec；imatinib mesilate；methanesulfonate;4-[(4-methylpiperazin-4-ium-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
• CAS: 220127-57-1
• 化学式: CH₄O₃S*C₂₉H₃₁N₇O
• 分子量: 589.718
• InChiKey: YLMAHDNUQAMNNX-UHFFFAOYSA-N

物化性质

• 熔点：
  214-224°C
• 溶解度：
  在水中的溶解度为10mg/mL，澄清
• 颜色/状态：
  White to off white to brownish or yellowish tinged crystalline powder

计算性质

• 辛醇/水分配系数(LogP)：
  4.09
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  149
• 氢给体数：
  3
• 氢受体数：
  10

ADMET

代谢

CYP3A4是负责伊马替尼代谢的主要酶。其他细胞色素P450酶，如CYP1A2、CYP2D6、CYP2C9和CYP2C19，在其代谢中起次要作用。人类循环中的主要活性代谢物是N-去甲基化的哌嗪衍生物，主要由CYP3A4形成。它显示出与伊马替尼相似的体外效力。这种代谢物的血浆AUC约为伊马替尼AUC的15%。

CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：有限的信息表明，母亲每日服用伊马替尼最高400毫克的剂量，会在乳汁中产生低水平的药物及其活性代谢物。尽管一些在母亲使用伊马替尼期间母乳喂养的婴儿似乎没有出现不良反应，但没有长期的可用数据。在更多数据可用之前，伊马替尼在母乳喂养期间应谨慎使用，并密切监测。国家综合癌症网络指南、制造商和一些作者建议在伊马替尼治疗期间及治疗结束后1个月内停止母乳喂养。 ◉ 对母乳喂养婴儿的影响：一名患有慢性髓细胞白血病的妇女在母乳喂养的前两个月内，每天口服伊马替尼400毫克，婴儿未出现不良反应。 一名患有慢性髓样白血病的妇女在怀孕期间和母乳喂养期间（具体时间未说明）近6个月的时间内，每天服用伊马替尼400毫克。她的婴儿据报道生长和发育正常。 一名患有慢性髓细胞白血病的妇女从怀孕第8周开始每天服用伊马替尼400毫克，并在母乳喂养期间（具体时间未说明）持续了8个月。婴儿是健康的，但在30个月大时修复了一个房间隔缺损。认为这与伊马替尼治疗无关。 一名患有费城染色体阳性慢性髓样白血病的孕妇在怀孕期间开始每天服用伊马替尼400毫克。分娩后，她的早产儿在出生后第五天中段之前喂食初乳，之后改为纯配方奶喂养。婴儿接受了早产儿呼吸暂停的治疗，并在生命第25天出院。在第一年的生活中，未观察到对生长或发育的不良影响。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Limited information indicates that maternal doses of imatinib up to 400 mg daily produce low levels of the drug and its active metabolite in milk. Although a few breastfed infants apparently experienced no adverse effects during maternal use of imatinib, no long-term data are available. Until more data are available, imatinib should be used only with careful monitoring during breastfeeding. National Comprehensive Cancer Network guidelines, the manufacturer and some authors recommend that breastfeeding be discontinued during imatinib therapy and for 1 month after therapy. ◉ Effects in Breastfed Infants:A woman receiving oral imatinib 400 mg daily for chronic myeloid leukemia breastfed her infant. No adverse effects were noted in the infant during the first 2 months of nursing. One woman with chronic myelogenous leukemia received imatinib 400 mg daily throughout pregnancy and during breastfeeding (extent not stated) for nearly 6 months postpartum. Her infant reportedly grew and developed normally. A woman with chronic myeloid leukemia received imatinib 400 mg daily starting at week 8 of pregnancy and continuing throughout 8 months of breastfeeding (extent not stated). The infant was healthy, but an atrial septal defect was repaired at 30 months of age. It was thought to be unrelated to imatinib therapy. A pregnant woman with Philadelphia chromosome-positive chronic myelogenous leukemia was started on imatinib 400 mg daily during pregnancy. After delivery, her preterm infant was fed colostrum until the middle of the fifth day postpartum when exclusive formula feeding was instituted. The infant was treated for apnea of prematurity and discharged on day 25 of life. No adverse effects on growth or development were noted during the first year of life. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

在这项研究中，进行了一项调查以研究同时给予伊马替尼和依达鲁比辛（一种具有血液抑制活性的蒽环类药物）对裸鼠和鼠骨髓细胞的影响。与仅接受伊马替尼或依达鲁比辛单独治疗的小鼠相比，当依达鲁比辛和伊马替尼同时给药时，双重治疗的小鼠显示出显著增加的死亡率。与仅接受依达鲁比辛治疗的小鼠相比，联合治疗诱导了更严重的粒细胞减少，并且恢复速度较慢。通常在依达鲁比辛治疗后在脾脏观察到的髓样化生在伊马替尼共同治疗的小鼠中不存在。双重治疗的动物的骨髓也显示出巨核细胞和髓系前体细胞数量的减少。在伊马替尼存在的条件下培养鼠骨髓细胞，抑制了SCF诱导的增殖和对依达鲁比辛治疗的恢复能力。结果表明，伊马替尼的同步给药增强了依达鲁比辛在体内和体外诱导的血细胞生成毒性。

In this study /an investigation was conducted to study/ the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. ... Results indicate that the simultaneous administration of imatinib enhances idarubicin-induced hematopoietic toxicity in vivo and in vitro.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在联用Gleevec（伊马替尼）和CYP3A4家族抑制剂（例如，酮康唑、伊曲康唑、红霉素、克拉霉素）时需谨慎。抑制细胞色素P450同工酶（CYP3A4）活性的物质可能会降低代谢并增加伊马替尼的浓度。

Caution is recommended when administering Gleevec /imatinib/ with inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concetrations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

CYP3A4活性诱导剂可能会增加代谢并降低伊马替尼的血浆浓度。诱导CYP3A4的共同用药（例如地塞米松、苯妥英、卡马西平、利福平、苯巴比妥或圣约翰草）可能会减少格列卫/伊马替尼的暴露量。…一位长期使用苯妥英的患者…给予每天350毫克格列卫的剂量，其AUC0-24大约是典型AUC0-24 20 ug/hr/mL的五分之一。这可能是苯妥英诱导CYP3A4的结果。

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or St. John's Wort) may reduce exposure to Gleevec /imatinib/. ...A patient on chronic therapy with phenytoin... given 350 mg daily dose of Gleevec had an AUC0-24 about one-fifth of the typical AUC0-24 of 20 ug/hr/mL. This probably reflects the induction of CYP3A4 by phenytoin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

伊马替尼会增加辛伐他汀（CYP3A4底物）的平均Cmax和AUC，分别增加2倍和3.5倍，这表明伊马替尼可能抑制了CYP3A4。在给予格列卫（伊马替尼）与治疗窗口狭窄的CYP3A4底物（例如，环孢素或匹莫齐特）时，应特别小心。格列卫将增加其他由CYP3A4代谢的药物的血药浓度（例如，三唑环安定药、二氢吡啶类钙通道阻滞剂、某些HMG-CoA还原酶抑制剂等）。

Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib. Particular caution is recommended when administering Gleevec /imatinib/ with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine or pimozide). Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

伊马替尼口服给药后吸收良好，给药后2-4小时内达到Cmax。胶囊剂型的平均绝对生物利用度为98%。在健康志愿者中口服给药后，伊马替尼及其主要活性代谢物N-去甲基衍生物的消除半衰期分别约为18小时和40小时。伊马替尼的平均AUC随着剂量的增加（在25毫克-1000毫克的范围内）而成比例增加。在重复给药时，伊马替尼的药代动力学没有显著变化，当格列卫每天一次给药时，稳态下的积累为1.5-2.5倍。在体外实验中，在伊马替尼的临床相关浓度下，与血浆蛋白的结合率约为95%，主要与白蛋白和α1-酸性糖蛋白结合。

Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability for the capsule formulation is 98%. Following oral administration in healthy volunteers, the elimination half-lives of imitanib and its major active metabolite, the N-desmethyl derivative, were approximately 18 and 40 hours, respectively. Mean imatinib AUC increased proportionally with increasing dose in the range 25 mg-1000 mg. There was no signficant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5-2.5 fold at steady state when Gleevec is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and (alpha)1-acid glycoprotein.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

粪便/消除/ - 68% 在7天内（20%的剂量未改变）；肾/消除/ - 13% 在7天内（5%的剂量未改变）。

Fecal /elimination/ - 68% within 7 days (20% of dose unchanged); Renal /elimination/ - 13% within 7 days (5% of dose unchanged).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

通常，一个50岁、体重50公斤的患者服用伊马替尼的清除率预计为8升/小时，而一个50岁、体重100公斤的患者的清除率将增加到14升/小时。然而，清除率在患者间的40%变异率并不意味着应根据体重和/或年龄调整初始剂量，但确实表明需要密切监测治疗相关毒性。

Typically, clearance of imitanib in a 50-year-old patient weighing 50 kg is expected to be 8 L/hr, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/hr. However, the inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment related toxicity.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在授乳期雌性大鼠中给予100毫克/公斤的伊马替尼...伊马替尼及其代谢物在乳汁中被广泛排泄。估计大约有1.%的母体剂量排泄到乳汁中，这相当于按单位体重计算给予婴儿的剂量是母体剂量的30%。

In lactating female rats administered 100 mg/kg ... imatinib and/or its metabolites were extensively excreted in milk. It is estimated that approximately 1.% of a maternal dose is excreted into milk, which is equivalent to a dose to the infant of 30% the maternal dose per unit body weight.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• WGK Germany：
  3
• 海关编码：
  2933990090
• 安全说明：
  S16,S26,S36/37/39
• 危险品运输编号：
  UN 1993 3/PG 2
• 危险类别：
  3
• 包装等级：
  II
• 危险标志：
  GHS07
• 危险性描述：
  H302
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 储存条件：
  -20°C冷冻库

SDS

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模块 1. 化学品
1.1 产品标识符
: Imatinib mesylate
产品名称
1.2 鉴别的其他方法
Imatinib methanesulfonate; STI-571; CGP 57148; Genfatinib; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-
methyl-3-{[4-(pyridin-3-yl)pyrim
1.3 有关的确定了的物质或混合物的用途和建议不适合的用途
仅用于研发。不作为药品、家庭或其它用途。

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模块 2. 危险性概述
2.1 GHS-分类
急性毒性, 经口 (类别 4)
2.2 GHS 标记要素，包括预防性的陈述
象形图
警示词 警告
危险申明
H302 吞咽有害。
警告申明
预防措施
P264 操作后彻底清洁皮肤。
P270 使用本产品时不要进食、饮水或吸烟。
事故响应
P301 + P312 如果吞咽并觉不适: 立即呼叫解毒中心或就医。
P330 漱口。
废弃处置
P501 将内容物/ 容器处理到得到批准的废物处理厂。
2.3 其它危害物 - 无

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模块 3. 成分/组成信息
3.1 物 质
: Imatinib methanesulfonate; STI-571; CGP 57148; Genfatinib; 4-[(4-
别名
methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrim
: C29H31N7O . CH4O3S
分子式
: 589.71 g/mol
分子量
组分 浓度或浓度范围
Imatinib mesylate
<=100%
化学文摘登记号(CAS 220127-57-1
No.)

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模块 4. 急救措施
4.1 必要的急救措施描述
一般的建议
请教医生。 向到现场的医生出示此安全技术说明书。
吸入
如果吸入,请将患者移到新鲜空气处。 如呼吸停止,进行人工呼吸。 请教医生。
皮肤接触
用肥皂和大量的水冲洗。 请教医生。
眼睛接触
用