伐地那非三水合盐酸盐 | 224785-90-4

• 物质功能分类: 生物化工 - 抑制剂 - 代谢(Metabolism)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 伐地那非三水合盐酸盐
• 中文别名: 盐酸瓦地那非三水合物；2-[2-乙氧基-5-(4-乙基-哌嗪-1-磺酰基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f]-[1,2,4]三联氮-4-酮单盐酸盐三水合物；盐酸伐地那非；伐地那非；瓦地那非
• 英文名称: vardenafil
• 英文别名: 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-imidazo[5,1-f] [1,2,4]triazin-4-one；Vardenafil；2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one
• CAS: 224785-90-4
• 化学式: C₂₃H₃₂N₆O₄S
• 分子量: 488.611
• InChiKey: SECKRCOLJRRGGV-UHFFFAOYSA-N

物化性质

• 熔点：
  230-235°C
• 密度：
  1.37
• 闪点：
  9℃
• 溶解度：
  >22.5mg/mL，溶于 DMSO
• LogP：
  2.5 at 23℃
• 物理描述：
  Solid
• 蒸汽压力：
  3.4X10-19 mm Hg at 25 °C /Estimated/
• 亨利常数：
  Henry's Law constant = 1.9X10-21 atm-cu m/mol at 25 °C /Estimated/
• 解离常数：
  pKa1= 4.72; pKa2= 6.21 (tertiary amine) /Estimated/
• 碰撞截面：
  225.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  118
• 氢给体数：
  1
• 氢受体数：
  8

ADMET

代谢

伐地那非主要通过肝脏酶CYP3A4代谢，CYP3A5和CYP2C异构体也有所贡献。主要循环代谢物M1是由伐地那非的哌嗪部分脱乙基产生的。M1对磷酸二酯酶的选择性轮廓与伐地那非相似，对PDE5的体外抑制效力为伐地那非的28%。

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil.

来源:DrugBank

代谢

肝脏代谢，主要通过CYP3A4，CYP3A5和CYP2C同工酶也有所贡献。主要循环代谢物M1是由伐地那非的哌嗪部分脱乙基产生的。M1还会进一步代谢。M1的血浆浓度大约是母体化合物的26%，占总药理活性的7%。这种代谢物显示出与伐地那非相似的磷酸二酯酶选择性特征，对PDE5的体外抑制效力为伐地那非的28%。

Hepatic metabolism, via CYP3A4, with contribution from CYP3A5 and CYP2C isoforms. Major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% of the parent compound and accounts for 7% of total pharmacologic activity. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

过量症状包括视力改变以及背部和肌肉疼痛。

Symptoms of overdose include vision changes and back and muscle pain.

来源:DrugBank

毒理性

• 肝毒性

在brentuximab vedotin的大规模临床试验的出版物中，通常没有提到ALT升高和临床上明显的肝损伤的发生率。在产品标签中描述的头颈部鳞状细胞癌的研究中，接受brentuximab vedotin和放疗的人中有45%出现ALT升高，而仅接受放疗的人中有22%出现升高，但高于上限五倍以上的升高很少见（2%对1%）。文献中有描述brentuximab vedotin治疗期间出现的短暂血清转氨酶升高的个别案例，通常发生在治疗的初期阶段。尽管如此，brentuximab vedotin的产品标签提到了严重的肝毒性，包括致命情况，并建议监测肝酶和胆红素水平。然而，没有已发表的描述归因于brentuximab的伴有黄疸的临床上明显肝损伤的情况。

In publications on the large scale trials of brentuximab vedotin, rates of ALT elevations and clinically apparent liver injury were usually not mentioned. In a study of squamous cell carcinoma of the head and neck described in the product label, ALT elevations occurred in 45% of persons receiving brentuximab vedotin and radiation therapy versus 22% of those receiving radiation alone, but elevations above 5 times the ULN were rare (2% vs 1%). Isolated instances of transient serum aminotransferase elevations have been described with brentuximab vedotin therapy in the literature, usually arising during the initial course of treatment. Nevertheless, the product label for brentuximab vedotin mentions serious hepatotoxicity including fatalities and recommends monitoring of liver enzyme and bilirubin levels. However, there have been no published descriptions of clinically apparent liver injury with jaundice attributable to brentuximab.

来源:LiverTox

毒理性

• 肝毒性

当用于实体器官移植的诱导治疗时，达利珠单抗并未与血清酶水平升高或临床上明显的肝脏损伤相关。虽然在器官移植时出现不良事件很常见，但并未发现接受达利珠单抗诱导治疗的患者比接受传统免疫抑制方案的患者更频繁地出现这些事件。 相比之下，在长期使用达利珠单抗治疗自身免疫疾病（如多发性硬化症）的研究中，报告了高达三分之一的患者出现了血清转氨酶水平的短暂和无症状升高，并且在使用达利珠单抗的患者中，有4%至6%的患者血清转氨酶水平升高超过正常上限的5倍，而安慰剂组和干扰素β治疗组的这一比例分别为1%和3%。这些血清酶水平升高通常是短暂和无症状的，但在罕见情况下会导致黄疸和有症状的急性肝损伤。在注册前的临床试验中，超过6个月使用达利珠单抗治疗的0.3%的患者出现了具有自身免疫特征的肝炎，至少有一名患者在停用单克隆抗体治疗后死亡。临床上明显的肝损伤通常在开始每月注射后的1到6个月内出现，但有些病例在治疗停止后不久就出现了。肝损伤的临床特征提示为免疫介导的肝炎，血清转氨酶水平显著升高，有时伴有自身抗体的形成、免疫球蛋白水平的增加或肝脏活检组织学显示急性肝细胞损伤伴淋巴细胞浸润，包括浆细胞。因为这些报告，达利珠单抗的产品标签中包含了关于肝损伤的黑框警告，建议在治疗前、治疗期间以及治疗后的几个月内进行前瞻性监测，并指出达利珠单抗禁用于有预先存在肝病的患者。 可能性评分：C（可能是临床上明显肝损伤的原因）。 达利珠单抗是一种强效的免疫抑制剂，可能能够引起慢性乙型肝炎的复发。然而，在预防器官排斥以及治疗难治性多发性硬化的使用中，并未与复发病例相关。在多发性硬化和葡萄膜炎的达利珠单抗试验中，并未报告乙型肝炎复发或丙型肝炎加重的病例，但早期试验通常排除了同时患有乙型或丙型肝炎的患者。 药物类别：单克隆抗体，移植剂，多发性硬化症治疗剂。

When given as a part of induction therapy for solid organ transplantation, daclizumab was not linked to instances of serum enzyme elevations or clinically apparent liver injury. While adverse events at the time of organ transplantation are common, they were not found to be more frequent in patients receiving induction therapy with daclizumab than in those given conventional immunosuppressive regimens. In contrast, in studies of long term daclizumab therapy for autoimmune conditions such as multiple sclerosis, transient and asymptomatic elevations of serum aminotransferase levels were reported in up to one third of patients, and rose to above 5 times ULN in 4% to 6% of daclizumab vs 1% of placebo and 3% of interferon beta treated subjects. These serum enzyme elevations were usually transient and asymptomatic, but in rare instances led to jaundice and symptomatic acute liver injury. In preregistration clinical trials, 0.3% of patients treated with daclizumab for more than 6 months developed hepatitis with autoimmune features, and at least one patient died despite discontinuation of the monoclonal antibody therapy. The onset of the clinically apparent liver injury was usually within 1 to 6 months after starting the monthly injections, but some cases arose shortly after discontinuation of treatment. The clinical features of the liver injury suggested an immune mediated hepatitis with marked elevations in serum aminotransferase levels sometimes accompanied by autoantibody formation, increased immunoglobulin levels or liver biopsy histology demonstrating acute hepatocellular injury with lymphocytic infiltrates including plasma cells. Because of these reports, daclizumab product labels include a black box warning about hepatic injury, recommend prospective monitoring before, during and for several months after treatment, and state that daclizumab is contraindicated in patients with preexisting liver disease. Likelihood score: C (probable cause of clinically apparent liver injury). Daclizumab is a potent immunosuppressive agent and may be capable of causing reactivation of chronic hepatitis B. However, its use in prevention of organ rejection as well as therapy of refractory multiple sclerosis has not been linked to cases of reactivation. In trials of daclizumab in multiple sclerosis and uveitis, cases of reactivation of hepatitis B or worsening of hepatitis C were not reported, but patients with coexisting hepatitis B or C were typically excluded from early phase trials. Drug Class: Monoclonal Antibodies, Transplant Agents, Multiple Sclerosis Agents

来源:LiverTox

毒理性

• 肝毒性

在大规模的临床试验中，使用efalizumab（依法利珠单抗）时，血清碱性磷酸酶水平常报告有轻度升高（比基线高2-3 U/L），但血清转氨酶值没有变化，并且没有记录到显著的丙氨酸转氨酶（ALT）升高或因单克隆抗体治疗而明显可见的肝脏损伤。在其获得批准并广泛用于临床后，有多份报告称因使用efalizumab治疗而导致的肝脏损伤，一例明显的乙型肝炎再激活（同时使用阿达木单抗治疗）以及一例自身免疫性肝炎的持续发展，该病例在使用efalizumab治疗8周后出现，并在停用单克隆抗体后未得到解决，需要使用皮质类固醇治疗。

In large clinical trials of efalizumab, serum alkaline phosphatase levels were often reported to be mildly elevated (by 2-3 U/L) compared to baseline, but serum aminotransferase values did not change and there were no reports of marked ALT elevations or clinically apparent liver injury due to the monoclonal antibody therapy. After its approval and wider scale clinical use, there were several reports of liver injury attributed to efalizumab therapy, one case of apparent reactivation of hepatitis B (with concurrent adalimumab therapy) and one case of a self-perpetuating autoimmune hepatitis, arising after 8 weeks of efalizumab therapy and not resolving with stopping the monoclonal antibody and requiring corticosteroid therapy.

来源:LiverTox

毒理性

• 肝毒性

尽管使用相当广泛，伐地那非并未与临床上明显的肝脏损伤案例相关联，在治疗期间血清酶水平升高的情况也很少见。与之相关的PDE5抑制剂，西地那非和他达拉非曾与孤立的、罕见的急性肝损伤和黄疸案例有关联。发病潜伏期从几天到3个月不等，损伤模式通常为胆汁淤积性。未观察到自身免疫和免疫过敏特征，所有案例都是自限性的，没有残留损伤或急性肝衰竭。目前尚不清楚伐地那非是否可能引起类似的急性肝损伤。

Despite fairly extensive use, vardenafil has not been associated with clinically apparent cases of liver injury and serum enzyme elevations during therapy are rare. The related PDE5 inhibitors, sildenafil and tadalafil have been linked to isolated, rare instances of acute liver injury and jaundice. The latency to onset ranged from a few days to 3 months and the pattern of injury was usually cholestatic. Autoimmune and immunoallergic features were not observed and all cases were self-limited without residual injury or acute liver failure. Whether vardenafil can cause a similar form of acute liver injury is unknown.

来源:LiverTox

吸收、分配和排泄

• 吸收

伐地那非迅速被吸收，绝对生物利用度大约为15%。

Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

口服给药后，伐地那非主要以代谢物的形式在粪便中排泄（约占口服剂量的91-95%），较少部分在尿液中排泄（约占口服剂量的2-6%）。

After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).

来源:DrugBank

吸收、分配和排泄

• 分布容积

208 升

208 L

来源:DrugBank

吸收、分配和排泄

• 清除

56 升/小时

56 L/h

来源:DrugBank

吸收、分配和排泄

蛋白质结合：极高，95%与血浆蛋白结合；可逆，且与总药物浓度无关。

Protein binding: Very high: 95% bound to plasma proteins; reversible and independent of total drug concentrations

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  F,Xn
• 安全说明：
  S16,S36/37
• 危险类别码：
  R11,R20/21/22,R36
• WGK Germany：
  1,2
• 危险品运输编号：
  UN 1648 3 / PGII
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P273,P301+P310
• 危险性描述：
  H301,H373,H410
• 储存条件：
  温度：20°C

制备方法与用途

生物活性 Vardenafil 是一种高效且选择性的磷酸二酯酶5 (PDE5) 抑制剂，IC50 值为 0.7 nM。它对 PDE1 的 IC50 为 180 nM、PDE6 的 IC50 为 11 nM，并且对 PDE2、PDE3 和 PDE4 具有较高的选择性，IC50 值均大于 1000 nM。Vardenafil 通过非竞争性抑制环磷酸鸟苷 (cGMP) 水解作用提高 cGMP 水平。该药物常用于研究勃起功能障碍。

靶点

酶	IC50 值（nM）
PDE5	0.7
PDE6	11
PDE1	180

体外研究 Vardenafil 特异性地抑制 PDE5 对 cGMP 的水解，其 IC50 值为 0.7 nM。

用途 伐地那非（Vardenafil）是目前最新的一种治疗勃起功能障碍 (ED) 的药物。相比西地那非，它有以下优势：剂量更小，仅需 20 mg；起效更快，在 15 至 30 分钟内见效。盐酸伐地那非（艾力达）因其强效、高选择性和良好的耐受性，为勃起功能障碍的治疗提供了新的选择。