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(1R,9S,12S,15R,18R,19R,21R,23S,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[30.3.1.0,4,9]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,12S,15R,18R,19R,21R,23S,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[30.3.1.0,4,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
英文别名
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,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
(1R,9S,12S,15R,18R,19R,21R,23S,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[30.3.1.0,4,9]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-WDSGEKFTSA-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。已在人类血液中检测到依维莫司的六个主要代谢物,包括三种单羟基化代谢物、两种水解开环产物以及一个依维莫司的磷脂酰胆碱共轭物。这些代谢物也在毒性研究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-中等免疫风险的器官排斥的预防。它还用于成人肝移植患者中异体移植物排斥的预防。人类暴露和毒性:人类对过量的报道经验非常有限。有一例2岁儿童意外摄入1.5毫克依维莫司的情况,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性质,可能使患者容易受到细菌、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,导致呼吸或肝功能衰竭)或致命的。使用依维莫司的患者还报告了致命的非传染性肺炎。在依维莫司(Afinitor)的临床试验中,血清肌酐浓度和蛋白尿有所增加。在使用依维莫司治疗的患者中,也观察到了肾衰竭(包括急性肾衰竭)的情况,其中一些是致命的。动物研究:依维莫司在为期2年的口服灌胃小鼠和大鼠中,每天剂量为0.9毫克/千克,并未引起致癌。在动物生殖研究中,将依维莫司口服给雌性大鼠,从交配前到器官形成期,诱发了胚胎-胎儿毒性,包括增加吸收、植入前和植入后损失、活胎儿数量减少、畸形(例如,胸骨裂)和骨骼发育迟缓。这些效应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)的情况下。在兔中,以0.8毫克/千克的口服剂量(9.6毫克/平方米)出现明显的胚胎毒性,表现为吸收增加。兔的效果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,动物从植入到哺乳期接受治疗。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)有所降低。后代的发展参数(形态发育、活动能力、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,在0.5毫克/千克及以上剂量时,睾丸形态受到影响,在5毫克/千克时,精子活力、精子头数和血浆睾酮浓度降低,导致雄性生育能力下降。在给药后13周检查的动物中,这些发现的可逆性有证据。在大鼠中,0.5毫克/千克的剂量导致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。在非临床研究中,依维莫司对雌性生育能力没有影响,但依维莫司穿过胎盘并对胎儿有毒。在细菌反向突变、小鼠淋巴瘤胸苷激酶试验、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,依维莫司并未表现出致突变性。
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
  • 肝毒性
血清酶升高发生在多达四分之一的服用依维莫司的患者中,但异常通常是轻微的、无症状的,并且是自限性的,很少需要调整剂量或停药。肝功能测试升高超过5倍ULN的情况只发生在1%到2%的治疗患者中。相比之下,尽管依维莫司在多种恶性和非恶性综合征中广泛使用,但没有将特异质、临床上明显的急性肝损伤与依维莫司治疗联系起来。血清酶、胆红素升高和肝炎被列为依维莫司产品标签中的潜在不良事件。因此,由于依维莫司导致的临床上明显的急性肝损伤并伴有黄疸的情况可能非常罕见,如果真的发生的话。 重要的是,依维莫司具有免疫抑制作用,癌症患者的治疗与乙型肝炎的再激活有关,这可能是严重的,甚至致命的。逆转血清转换(在预先存在乙型肝炎抗体的个体中发展HBsAg,无论是抗-HBs还是抗-HBc)也已有报道。 可能性评分:E*(未经证实,也不太可能是临床上明显肝损伤的原因,但能够诱导乙型肝炎的再激活)。
Serum enzyme elevations occur in up to a quarter of patients taking everolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Liver test elevations above 5 times ULN occur in only 1% to 2% of treated patients. In contrast, idiosyncratic, clinically apparent acute liver injury has not been linked to everolimus therapy despite its wide scale use in several malignant and non-malignant syndromes. Elevations in serum enzymes and bilirubin and hepatitis are listed as potential adverse events in the product label for everolimun. Thus, acute clinically apparent liver injury with jaundice due to everolimus is probably quite rare, if it occurs at all. Importantly, everolimus is immunosuppressive and therapy in patients with cancer has been associated with episodes of reactivation of hepatitis B, which can be severe and even fatal. Reverse seroconversion (development of HBsAg in a person with preexisting antibody to hepatitis B, either anti-HBs or anti-HBc) has also been reported. Likelihood score: E* (unproven and also unlikely cause of clinically apparent liver injury but capable of inducing reactivation of hepatitis B).
来源:LiverTox
毒理性
  • 相互作用
使用HMG-CoA还原酶抑制剂(如洛伐他汀或辛伐他汀)在肾移植患者中进行的依维莫司与环孢素的临床试验中强烈不推荐,因为HMG-CoA还原酶抑制剂与环孢素之间存在相互作用。Zortress的制造商建议,在接受依维莫司和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血脂药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)
毒理性
  • 相互作用
在健康个体中进行的研究表明,单剂量依维莫司与阿托伐他汀(CYP3A4底物)或普伐他汀(非CYP3A4底物和P-糖蛋白底物)之间没有临床重要的药代动力学相互作用;血浆中HMG-CoA还原酶的生物活性也没有受到显著影响。因此,当依维莫司与阿托伐他汀或普伐他汀同时使用时,不需要调整剂量。在一项群体药代动力学分析中,辛伐他汀(CYP3A4底物)并未影响依维莫司的清除。Zortress的生产商警告,这些结果不能推广到其他HMG-CoA还原酶抑制剂。
Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase bioactivity in plasma also was not substantially affected. Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently. In a population pharmacokinetic analysis, simvastatin (a CYP3A4 substrate) did not affect clearance of everolimus. The manufacturer of Zortress cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
与依维莫司联用血管紧张素转换酶(ACE)抑制剂可能会增加血管性水肿的风险。如果必要的话,应该考虑在依维莫司治疗的患者中使用其他抗高血压药物。
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors with everolimus may increase the risk of angioedema. The use of alternative antihypertensive agents should be considered in everolimus-treated patients, if necessary.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
依维莫司的血液到血浆比率取决于浓度,在5 ng/mL到5000 ng/mL的范围内从17%变化到73%。在健康受试者和中度肝功能损害的患者中,血浆蛋白结合率大约为74%。在维持性肾脏移植患者中,单次给药药代动力学研究的终末相的表观分布容积(Vz/F)为342至107升(范围128至589升)。
The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
依维莫司的血浆浓度比例,在5至5000 ng/mL的浓度范围内呈浓度依赖性,为17%至73%。在癌症患者中,给予阿芬太10 mg/天的血药浓度下,被血浆限制的依维莫司的量大约为20%。在健康受试者和中度肝功能损害的患者中,血浆蛋白结合率大约为74%。
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在给予晚期实体瘤患者服用阿芬太利片后,口服剂量从5毫克到70毫克,血药浓度峰值在给药后1到2小时内达到。单次给药后,Cmax(血药浓度峰值)与5毫克至10毫克每日剂量的给药呈剂量正比。在20毫克及以上的单次剂量中,Cmax的增加小于剂量正比,然而AUC(血药浓度-时间曲线下面积)在5毫克到70毫克的剂量范围内显示剂量正比。在每日一次给药后,稳态血药浓度在2周内达到。
After administration of Afinitor tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
没有针对癌症患者进行特定的消除研究。在给予接受环孢素治疗的患者单次3毫克的放射性标记的依维莫司后,80%的放射性物质从粪便中回收,而5%通过尿液排出。原药在尿液或粪便中未检测到。依维莫司的平均消除半衰期大约为30小时。
No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.
来源:Hazardous Substances Data Bank (HSDB)

同类化合物

马杜霉素II 雷帕霉素 长川霉素 达福普丁甲磺酸 西罗莫司脂化物 蛎灰菌素A 子囊霉素 威里霉素 唑他莫司 吡美莫司 双氢他克莫司 去甲氧基雷帕霉素 化合物 T32504 化合物 T25424 依维莫司 他克莫司杂质5 他克莫司31-DMT 他克莫司 乌米里莫斯 FK-506一水合物 8-表他克莫司 8,9,14,15,24,25,26,26alpha-八氢-14-羟基-4,12-二甲基-3-(1-甲基乙基)-(3R,4R,5E,10E,12E,14S,26alphaR)-3H-21,18-次氮基-1H,22H-吡咯并[2,1-c][1,8,4,19]二氧杂二氮杂二十四环-1,7,16,22(4H,17H)-四酮 42-O-[2-[[羟基[2-(三甲基铵)乙氧基]亚膦酰基]氧基]乙基]雷帕霉素内盐 42-(二甲基亚膦酰)雷帕霉素 42-(2-四唑基)雷帕霉素 40-O-[2-(叔丁基二甲硅基)氧代]乙基雷帕霉素 37-去亚甲基24,33-二-O-(叔-丁基二甲基硅烷基)-37-氧代-FK-506 31-O-去甲基-Fk506 28-O-甲基-雷帕霉素 24,33-二-O-(叔-丁基二甲基硅烷基)-37,38-去氢-37,38-二羟基-FK-506 24,32-双-O-(tert-butyldimethylsilyl)-他克莫司 22-羟基-33-叔-丁基二甲基硅烷基氧基-异-FK-506 2-甲氧基-5-硝基嘧啶-4-胺 19-表FK-506 15-O-去甲基长川霉素 13-O-去甲基子囊霉素 (E/Z)-FK-50626,28-烯丙酸酯 (2S,5S,6R,10R,11S)-10-庚基-6-羟基-4,11-二甲基-5-(苯基甲基)-2-丙-2-基-1,9-二氧杂-4-氮杂环十二烷-3,8,12-三酮 (1R,2R,4S)-4-{(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-二羟基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五氧代-11,36-二氧杂-4-氮杂三环[30.3.1.04,9]三十六碳-16,24,26,28-四烯-12-基]丙基}-2-甲氧基环己基2,2,5-三甲基-1,3-二恶烷-5-羧酸酯 (21S)-1-aza-4,4-dimethyl-6,19-dioxa-2,3,7,20-tetraoxobicyclo<19.4.0>pentacosane CCI-779 boronate rapamycin (-)-spongedepsin (1R,9S,12SR,15R,16E,18R,19R,21R,23S,24E,26E,28E,32SR,35R)-1,18-dihydroxy-30-(3-hydroxypropoxy)-19-methoxy-12-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-(3-phenylpropoxy)cyclohexyl]-1-methylethyl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone rapamycin 42-hemiadipate Rapamycin 42-ester with 4-methylpiperazine-1-carboxylic acid rapamycin O-[(S)-2,3-dihydroxypropyloxycarbonyl]rapamycin 29-epirapamycin 40-O-tert-butyldimethylsilyl rapamycin