fluvastatin | 93957-54-1

• 物质功能分类: 原料药 - 循环系统用药 - 调节血脂药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: fluvastatin
• 英文别名: [3H]-(+)-Fluvastatin；(+)-Fluvastatin；(3R, 5S, 6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3, 5-dihydroxyhept-6-enoic acid；(3R,5S,6E)-7-[3-(4-fluorophenyl )-1-(propan-2-yl)-1H-indol-2-yl]-3,4-dihydroxyhept-6-enoic acid；(3R,5S,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid；(+)-3R,5S-fluvastatin；Lescol；(E,3R,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic acid
• CAS: 93957-54-1
• 化学式: C₂₄H₂₆FNO₄
• mdl: MFCD00865715
• 分子量: 411.473
• InChiKey: FJLGEFLZQAZZCD-MCBHFWOFSA-N

物化性质

• 熔点：
  193.9-196.9 °C
• 沸点：
  681.8±55.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 溶解度：
  水 25 mg/ml DMSO 100 mg/ml 乙醇 25 mg/ml
• 蒸汽压力：
  1.91X10-16 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 5.58X10-17 atm-cu m/mol at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Fluvastatin sodium hydrate/
• 分解：
  Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen fluoride, sodium oxides. /Fluvastatin sodium hydrate/
• 解离常数：
  pKa = 4.5 (carboxy) (est)
• 碰撞截面：
  200.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.291
• 拓扑面积：
  82.7
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

体外数据表明，氟伐他汀的代谢涉及多种细胞色素P450（CYP）同工酶。CYP2C9同工酶主要参与氟伐他汀的代谢（约75%），而CYP2C8和CYP3A4同工酶的参与程度则要低得多，即分别大约为5%和大约20%。

In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟伐他汀在肝脏中被代谢，主要是通过吲哚环在5和6位置的羟基化。N-脱烷基化和侧链的β-氧化也有发生。羟基代谢物具有一些药理活性，但不会在血液中循环。氟伐他汀有两种对映异构体。氟伐他汀的两种对映异构体以相似的方式被代谢。

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5 and 6 positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：氟伐他汀是一种抗胆固醇药物和羟甲戊二酸辅酶A还原酶抑制剂。人类暴露和毒性：已经报道了使用氟伐他汀胶囊和这类药物中的其他药物导致的横纹肌溶解伴急性肾功能衰竭。在使用他汀类药物，包括氟伐他汀的患者中，有罕见报告肝衰竭致死的病例。如果在使用氟伐他汀治疗期间出现严重的肝损伤、临床症状和/或高胆红素血症或黄疸，应立即中断治疗。氟伐他汀胶囊在孕妇或可能怀孕的妇女中是禁忌的。正常怀孕期间，血清胆固醇和甘油三酯水平会升高，胆固醇或胆固醇衍生物对胎儿发育至关重要。当孕妇使用氟伐他汀胶囊时，可能会对胎儿造成伤害。药物不良反应报告显示，与.stat治疗相关的神经精神反应的发生。它们包括行为改变；认知和记忆障碍；睡眠障碍；和性功能障碍。动物研究：在小鼠中进行的剂量为0.3、15和30 mg/kg/日的致癌性研究中发现，与大鼠相似，30 mg/kg/日时雄性和雌性小鼠前胃鳞状细胞乳头状瘤有统计学意义的增加，15 mg/kg/日时雌性小鼠前胃鳞状细胞乳头状瘤有统计学意义的增加。在大鼠中，氟伐他汀以12 mg/kg/日的剂量出现骨骼发育迟缓，在兔中以10 mg/kg/日的剂量出现骨骼发育迟缓。在以下研究中，无论是否进行代谢激活，均未观察到突变性：使用突变株的Salmonella typhimurium或Escherichia coli进行的微生物突变试验；在BALB/3T3细胞中进行恶性转化试验；在大鼠原代肝细胞中进行非计划性DNA合成；在V79中国仓鼠细胞中进行的染色体畸变试验；HGPRT V79中国仓鼠细胞。此外，在大鼠或小鼠微核试验中也未发现突变性。

IDENTIFICATION AND USE: Fluvastatin is anticholesteremic agent and hydroxymethylglutaryl-CoA reductase inhibitor. HUMAN EXPOSURE AND TOXICITY: Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class. There have been rare reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin, promptly interrupt therapy. Fluvastatin capsules are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women. Adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioral alterations; cognitive and memory impairments; sleep disturbance; and sexual dysfunction. ANIMAL STUDIES: The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. Fluvastatin produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. No evidence of mutagenicity was observed in vitro, with or without metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

氟伐他汀治疗与1%至5%的患者出现轻度、无症状且通常是暂时的血清转氨酶升高有关，但在超过3倍ULN水平的患者中大约为1%。在大规模前瞻性监测研究的汇总分析中，出现正常以上的ALT升高在多达5%的患者中发生；在氟伐他汀治疗的患者中，ALT水平超过正常上限3倍的发生率为1.1%，而安慰剂接受者为0.3%。这些升高在使用较高剂量氟伐他汀时更为常见。大多数这些升高是自限性的，不需要调整剂量。氟伐他汀是与血清转氨酶升高最相关的他汀类药物，也是与症状性肝损伤最高发生率相关的药物，然而，明显的、临床上可见的氟伐他汀引起的肝损伤仍然非常罕见，估计在使用氟伐他汀的每10,000人年中有1.7例发生。在报告的少数病例中，临床损伤的发病时间在1到4个月之内，损伤模式通常是胆汁淤积性或混合性。皮疹、发热和嗜酸性粒细胞增多不常见。至少有一例具有自身免疫特征的病例已被描述。大多数病例在发病后几个月内解决。急性肝衰竭和死亡罕见案例被归因于氟伐他汀。

Fluvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 5% of patients but in levels above 3 times ULN is approximately 1%. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in up to 5% of patients; ALT levels of above 3 times the upper limit of normal (ULN) occurred in 1.1% of fluvastatin treated versus 0.3% of placebo recipients. These elevations were more common with higher doses of fluvastatin. Most of these elevations were self-limited and did not require dose modification. Fluvastatin is the statin most commonly associated with serum aminotransferase elevations and the highest rates of symptomatic liver injury, yet frank, clinically apparent hepatic injury from fluvastatin is still quite rare estimated to occur in 1.7 per 10,000 person years of use. In the few cases that have been reported, the onset of clinical injury has been within 1 to 4 months, the pattern of injury is typically cholestatic or mixed. Rash, fever and eosinophilia are uncommon. At least one case with features of autoimmunity has been described. Most cases resolve within a few months of onset. Rare cases of acute liver failure and death have been attributed to fluvastatin.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：氟伐他汀

Compound:fluvastatin

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

吸收、分配和排泄

基于动物数据，氟伐他汀在母乳中的比例约为2:1（母乳：血浆）。

/MILK/ Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

服用胶囊后，氟伐他汀在不到1小时内达到峰值浓度。服用10毫克剂量后的绝对生物利用度为24%（范围9%至50%）。

Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氟伐他汀与血浆蛋白的结合率为98%。平均分布容积（VDss）估计为0.35 L/kg。在治疗浓度下，华法林、水杨酸和格列本脲不会影响氟伐他汀的蛋白结合。

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

非诺伐他汀缓释片 80 毫克在空腹条件下、低脂餐后或低脂餐后 2.5 小时达到峰值浓度大约需要 3 小时。与空腹条件下给药的非诺伐他汀即释胶囊相比，缓释片的平均相对生物利用度大约为 29%（范围：9% 至 66%）。高脂餐后给药会延迟吸收（Tmax：6 小时）并使缓释片的生物利用度提高约 50%。然而，高脂餐后非诺伐他汀钠缓释片达到的最大浓度低于单次剂量或每日两次剂量的 40 毫克非诺伐他汀胶囊后的峰值浓度。

Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low fat meal, or 2.5 hours after a low fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range: 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high fat meal delayed the absorption (Tmax: 6 hr) and increased the bioavailability of the extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• WGK Germany：
  3
• 危险类别：
  3
• 安全说明：
  S23,S26,S37
• 危险类别码：
  R36/37/38,R42/43
• 包装等级：
  III
• 危险品运输编号：
  UN 3272 3/PG 3

制备方法与用途

降胆固醇药物：氟伐他汀 氟伐他汀简介

氟伐他汀（fluvastatin）是第一个全化学合成的降胆固醇药物，属于羟甲戊二酰辅酶A (HMG-CoA) 还原酶抑制剂。它通过将HMG-CoA转化为3-甲基-3, 5-二羟戊酸来发挥作用。

与洛伐他汀、新伐他汀和普伐他汀等已上市的天然或半合成HMG-CoA还原酶抑制剂相比，氟伐他汀具有结构相对简单、作用选择性高及不良反应发生率低的优点。因此，它是一种优秀的降血脂药。

药代动力学 吸收

健康志愿者空腹服用氟伐汀钠后，吸收迅速且完全（98%）。餐后服用会减慢其吸收速度。在服20 mg或40 mg氟伐汀钠胶囊1小时后，血浆峰浓度分别约为140 ng/mL和365 ng/mL。

分布

表观分布容积(Vz/f) 为330 L。超过98%的循环药物与血浆蛋白结合，且这种结合不受血药浓度的影响。

代谢

氟伐他汀主要通过β氧化、吲哚环5、6位的羟化和1位异丙基的丢失途径进行体内代谢。在人肝微粒体中，它主要被细胞色素P450同功酶CYP2C9亚族代谢。

药物相互作用

1. 消胆胺能增强氟伐他汀降胆固醇效能。
2. 与西咪替丁、雷尼替丁或奥美拉唑同用，可使本品血浓度升高，清除率下降。
3. 与利福平同用则降低本品血药浓度，增加清除率。
4. 与地高辛合用，可使地高辛血浓度升高。

作用和用途

氟伐他汀为人工合成品，化学结构类似普伐他汀。它通过抑制HMG-CoA还原酶和其他途径降胆固醇，在用药后4周达到最大疗效，继续用药疗效稳定。

适应症

用于动物脂肪和胆固醇饮食所致的高胆固醇血症（Ⅱa和Ⅱb）的治疗。

合成路线

氟伐他汀的活性成分为氟伐他汀钠。其合成路线如下：

参考资料：李玉龙, 刘菊. 氟伐他汀钠的合成工艺研究[J], 药物资讯, 20XX, X(X): XX-XX。

注意事项

1. 尽管氟伐他汀仅小部分药物经CYP3A4代谢，但应慎用。
2. 监测病人使用本品时出现的肌肉痛、触痛及突然衰弱，并注意不适和发热症状。如发现肌酐磷酸激酶（CPK）水平升高或肌痛即停止给药。
3. 在活动型肝炎、重症肝炎、孕妇、哺乳期妇女中禁用。与树脂类药物合用时，需间隔4小时避免降低生物利用度。
4. 给药前曾用过利福平的患者，将降低氟伐他汀的生物利用度50%。
5. 肝功能不正常者禁用。给药前或期间必须进行肝功测定。
6. 消胆胺可加强本品的药理活性。
7. 西咪替丁、雷尼替丁、奥美拉唑使本品Gmax 和AUC显著升高，血浆清除率下降。
8. 氟伐他汀与利福平同时使用则降低血药浓度，清除率升高。
9. 本品使地高辛Gmax升高，给药时应注意监护。

反应信息

• 作为反应物：
  描述：

  fluvastatin 在 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 生成 氟伐他汀内酯
  参考文献：
  名称：

  Synthesis and Hydroxyapatite Binding Activity of Bisphosphonate-Statin Conjugates (SUPPLEMENTAL FILE)

  摘要：

  为了开发一种将同化制剂他汀类药物输送到骨骼的方法，使用了一种骨骼靶向双膦酸盐作为药物载体。我们合成了四种他汀类药物-双膦酸盐共轭物，并通过羟基磷灰石吸收法在体外检测了它们的骨矿物质亲和性。这些共轭物与羟基磷灰石具有很高的结合活性，这意味着改性他汀类药物具有潜在的骨靶向特性。

  DOI：

  10.2174/157017809788681356
• 作为产物：
  描述：

  (3R,5S)-氟伐他汀钠盐 在 sodium hydrogen sulfate 作用下， 以 水 、 乙酸乙酯 为溶剂， 生成 fluvastatin
  参考文献：
  名称：

  Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase

  摘要：

  本发明提供了物质组合物、试剂盒和它们在治疗MAP激酶相关疾病和/或HMG-CoA还原酶相关疾病中的应用的方法。具体而言，本发明提供了用于通过抑制p38α MAP激酶和/或HMG-CoA还原酶来治疗动物主体的炎症和/或心血管疾病的组合物，以及提供这些组合物的配方和给药方式。本发明还提供了用于有理设计MAP激酶、HMG-CoA还原酶或两者的抑制剂的方法，用于实施本发明。

  公开号：

  US20050261354A1

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• New Drug Delivery System for Crossing the Blood Brain Barrier
  申请人：Lipshutz H. Bruce

  公开号：US20070203080A1

  公开（公告）日：2007-08-30

  New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.

  新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。