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(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

中文名称
——
中文别名
——
英文名称
(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
英文别名
——
(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone化学式
CAS
——
化学式
C53H83NO14
mdl
——
分子量
958.2
InChiKey
HKVAMNSJSFKALM-XKYNZCQCSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

计算性质

  • 辛醇/水分配系数(LogP):
    5.9
  • 重原子数:
    68
  • 可旋转键数:
    9
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.75
  • 拓扑面积:
    205
  • 氢给体数:
    3
  • 氢受体数:
    14

ADMET

代谢
依维莫司是CYP3A4和PgP的底物。口服给药后,依维莫司是人类血液中的主要循环成分。已经在人类血液中检测到依维莫司的六种主要代谢物,包括三种单羟基化代谢物,两种解开环产物,以及一种依维莫司磷脂胆碱共价结合物。这些代谢物也在毒性研究中使用的动物种类中被识别,并且显示出比依维莫司本身大约低100倍的活动性。
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
识别和使用:依维莫司是一种哺乳动物雷帕霉素靶蛋白(mTOR)激酶的抑制剂,是一种抗肿瘤剂和大环内酯类免疫抑制剂依维莫司(商品名Afinitor)用于治疗某些类型的乳腺癌、胰腺神经内分泌肿瘤、肾细胞癌、伴有结节性硬化症的肾血管平滑肌脂肪瘤以及伴有结节性硬化症的室管膜下巨细胞星形细胞瘤。依维莫司(商品名Zortress)用于成人肾移植患者中低-中度免疫风险的器官排斥预防。它还用于成人肝移植患者的异体移植物排斥预防。人类暴露和毒性:关于人类过量服用的报道非常有限。有一例2岁儿童意外摄入1.5毫克依维莫司,未观察到不良反应。单次剂量高达25毫克的移植患者已接受治疗,具有可接受的急性耐受性。在没有环孢素的情况下,单次剂量高达70毫克的患者已接受治疗,具有可接受的急性耐受性。依维莫司具有免疫抑制作用,可能使患者易患细菌、真菌、病毒或原虫感染,包括机会性感染。其中一些感染是严重的(例如,导致呼吸或肝衰竭)或致命的。还报告了与依维莫司相关的致命非感染性肺炎。在依维莫司(Afinitor)的临床试验中,已报告血清肌酐浓度升高和蛋白尿。在接受依维莫司治疗的病人中也观察到了肾衰竭(包括急性肾衰竭)的情况,有些是致命的。动物研究:在小鼠和大鼠中,通过口服灌胃每天给药0.9毫克/千克,持续2年,未发现致癌性。在动物生殖研究中,给雌性大鼠在交配前和器官形成期间口服依维莫司,诱发了胚胎-胎儿毒性,包括增加吸收、着床前和着床后损失、活胎儿数量减少、畸形(例如,胸骨裂)和骨骼发育迟缓。这些影响发生在没有母体毒性的情况下。在大鼠中,胚胎-胎儿毒性发生在剂量大于或等于0.1毫克/千克(0.6毫克/平方米)时。在兔中,以0.8毫克/千克(9.6毫克/平方米)的口服剂量发生明显的胚胎毒性,表现为吸收增加。兔中的这种效应发生在母体毒性的存在下。在大鼠的产前和产后发育研究中,动物从着床期到哺乳期接受给药。在0.1毫克/千克(0.6毫克/平方米)的剂量下,对分娩和哺乳或母体毒性迹象没有不良影响;然而,后代体重(与对照组相比减少多达9%)和存活率(大约5%死亡或丢失)有所下降。后代的发展参数(形态发育、运动活动、学习或生育评估)没有药物相关的影响。在大鼠的13周雄性生育口服灌胃研究中,0.5毫克/千克及以上的剂量影响了睾丸形态,5毫克/千克的剂量降低了精子活力、精子头数和血浆睾酮浓度,导致雄性生育能力下降。在给药后13周检查的动物中,这些发现具有可逆性的证据。大鼠的0.5毫克/千克剂量导致AUCs在临床暴露范围内,而5毫克/千克的剂量导致AUCs大约是人类接受0.75毫克每日两次的5倍。依维莫司在非临床研究中未影响雌性生育能力,但依维莫司穿过胎盘并对胎儿有毒。在细菌反向突变、小鼠淋巴瘤胸腺嘧啶激酶试验、使用V79中国仓鼠细胞的染色体畸变试验或小鼠微核试验中,依维莫司每日两次剂量为500毫克/千克的活体试验中,未发现诱变性。
IDENTIFICATION AND USE: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent and macrolide immunosuppressive agent. Everolimus (brand name Afinitor) is used in the treatment of certain types of breast cancers, neuroendocrine tumors of pancreatic origin, renal cell carcinoma, renal angiomyolipoma with tuberous sclerosis complex, and subependymal giant cell astrocytoma with tuberous sclerosis complex. Everolimus (brand name Zortress) is used for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. It is also used for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. HUMAN EXPOSURE AND TOXICITY: Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including opportunistic infections. Some of these infections have been severe (e.g., resulting in respiratory or hepatic failure) or fatal. Fatal noninfectious pneumonitis also has been reported with everolimus. Increases in serum creatinine concentrations and proteinuria have been reported in clinical trials with everolimus (Afinitor). Cases of renal failure (including acute renal failure), some with a fatal outcome, also have been observed in everolimus-treated patients. ANIMAL STUDIES: Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses of 0.9 mg/kg. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses greater than or equal to 0.1 mg/kg (0.6 mg/sq m). In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/sq m. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/sq m), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (approximately 5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post-dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily. Everolimus did not affect female fertility in nonclinical studies, but everolimus crossed the placenta and was toxic to the conceptus. Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or in vivo following two daily doses of 500 mg/kg in the mouse micronucleus assay.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
使用HMG-CoA还原酶抑制剂(如洛伐他汀辛伐他汀)在肾移植患者中进行的依维莫司环孢素的临床试验中强烈不推荐,因为HMG-CoA还原酶抑制剂环孢素之间存在相互作用。Zortress的生产商建议,在接受依维莫司环孢素治疗的同时正在接受HMG-CoA还原酶抑制剂和/或纤维酸衍生物的患者中,应监测可能发生的横纹肌溶解症和其他不良反应,这些不良反应在这些降脂药物的处方信息中有描述。
Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine. The manufacturer of Zortress recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.
来源:Hazardous Substances Data Bank (HSDB)