(+)-(3R,5S)-fluvastatin

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (+)-(3R,5S)-fluvastatin
• 英文别名: (E,3R,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoate
• 化学式: C24H25FNO4-
• 分子量: 410.5
• InChiKey: FJLGEFLZQAZZCD-MCBHFWOFSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  85.5
• 氢给体数：
  2
• 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

• 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。氟伐他汀是最常与血清转氨酶升高和症状性肝损伤最高发生率相关的他汀类药物，然而，氟伐他汀引起的明显、临床上可见的肝损伤仍然相当罕见，估计在使用10,000人年中有1.7例发生。在报告的少数病例中，临床损伤的发作通常在1到4个月内，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情况被描述。大多数病例在发病后几个月内解决。

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.

来源:LiverTox

毒理性

• 相互作用

肌病病例，包括横纹肌溶解症，已经报告了与秋水仙碱联合使用氟伐他汀的情况，在开具氟伐他汀与秋水仙碱联合处方的时应谨慎。

Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在使用香豆素类抗凝剂的同时服用其他HMG-CoA还原酶抑制剂的患者中，已经报道了出血和/或凝血酶原时间增加的情况。因此，当开始使用氟伐他汀钠或更改氟伐他汀钠剂量时，接受华法林型抗凝剂治疗的患者应密切监测其凝血酶原时间。

Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

非诺伐他汀与苯妥英联合用药增加了苯妥英的暴露量。在开始非诺伐他汀治疗或改变非诺伐他汀剂量时，应继续适当监测患者。

Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when fluvastatin therapy is initiated or when fluvastatin dose is changed.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

非诺贝特和格列本脲的联合用药增加了格列本脲的暴露。正在联合使用格列本脲和非诺贝特的病人应继续适当监测。

Concomitant administration of fluvastatin and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and fluvastatin should continue to be monitored appropriately.

来源:Hazardous Substances Data Bank (HSDB)

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。与非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%）。高脂餐会延迟吸收（Tmax：6 小时）并使缓释片的生物利用度增加约 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)