1-hydrazinophthalazine | 1044569-46-1

• 物质功能分类: 有机原料 - 肼或胲的有机衍生物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 1-hydrazinophthalazine
• 英文别名: Hydralazine；hydralazin；phthalazin-1-ylhydrazine
• CAS: 1044569-46-1
• 化学式: C₈H₈N₄
• mdl: MFCD00599497
• 分子量: 160.178
• InChiKey: RPTUSVTUFVMDQK-UHFFFAOYSA-N

物化性质

• 沸点：
  353.3±25.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 熔点：
  172-173 °C
• 溶解度：
  <1mg/mL
• 保留指数：
  1530;1528

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  63.8
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

乙酰化是肼屈嗪的一种次要代谢途径；主要的代谢途径是羟基化随后是葡萄糖醛酸化。肼屈嗪有5种已知的代谢途径。肼屈嗪可以被代谢为酞嗪或α-酮戊二酸肼。这些代谢物可以进一步转化为酞嗪酮或肼屈嗪可以直接代谢为酞嗪酮。肼屈嗪可以经历一个可逆的转化，形成活性肼屈嗪丙酮肼。肼屈嗪会自发转化为活性丙酸肼或丙酸肼三环脱水产物，这些代谢物可以在这两种形式之间相互转化。肼屈嗪可以被转化为肼酞嗪酮，后者进一步转化为活性乙酰肼酞嗪酮。肼屈嗪可以进行的最后一个代谢过程是转化为一种未命名的肼屈嗪代谢物，该代谢物进一步代谢为3-甲基-s-三唑酞嗪（MTP）。MTP可以被代谢为9-羟基-甲基三唑酞嗪或3-羟基-甲基三唑酞嗪；后者转化为三唑酞嗪。

Acetylation is a minor metabolic pathway for hydralazine; the major pathway is hydroxylation followed by glucuronidation. There are 5 identified metabolic pathways for hydralazine. Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinone or hydralazine can be metabolized directly to phthalazinone. Hydralazine can undergo a reversible converstion to the active hydralazine acetone hydrazone. Hydralazine is spontaneously converted to the active pyruvic acid hydrazone or the pyruvic acid hydrazone tricyclic dehydration product, and these metabolites can convert back and forth between these 2 forms. Hydralazine can be converted to hydrazinophthalazinone, which is further converted to the active acetylhydrazinophthalazinone. The final metabolic process hydralazine can undergo is the conversion to an unnamed hydralazine metabolite, which is further metabolized to 3-methyl-s-triazolophthalazine (MTP). MTP can be metabolized to 9-hydroxy-methyltriazolophthalazine or 3-hydroxy-methyltriazolophthalazine; the latter is converted to triazolophthalazine.

来源:DrugBank

代谢

海普瑞拉嗪已知的人体代谢物包括海普瑞拉嗪N-乙酰化物。

Hydralazine has known human metabolites that include hydralazine N-acetyl.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

血清转氨酶升高在肼屈嗪治疗中被认为是不常见的。然而，肼屈嗪与急性肝损伤伴黄疸的病例以及迟发性狼疮样综合征有明确的关联。描述了两种与肝损伤相关的临床模式，分别与短期（2至6周）或长期（2个月至超过1年）潜伏期相关。临床上明显的肝损伤通常是肝细胞型的，尽管也报道了胆汁淤积型（案例1）。在短期潜伏期的病例中，皮疹、发热和嗜酸性粒细胞增多是常见的，发作通常是突然和严重的，并且恢复迅速。在长期潜伏期（案例2）的病例中，发作更为隐匿，肝活检可能类似于慢性肝炎并显示纤维化，并且常存在自身抗体。晚期肝炎也可能伴随肼屈嗪引起的狼疮样综合征，特别是在高剂量治疗6个月或更长时间时。恢复可能需要较长时间。在因结构相关抗高血压药物二肼屈嗪（在欧洲可用，但在美国不可用）导致肝毒性的患者中，已经识别出针对P450系统（CYP 1A2）异构体的自身抗体，与肼屈嗪相比，二肼屈嗪与更高的肝毒性率相关。

Serum aminotransferase elevations during hydralazine therapy are considered uncommon. However, hydralazine has been clearly linked to cases of acute liver injury with jaundice as well as a delayed lupus-like syndrome. Two clinical patterns of hepatic injury have been described, associated with either a short (2 to 6 weeks) or long (2 months to more than a year) latency period. The clinically apparent liver injury is usually hepatocellular, although cholestatic forms have also been reported (Case 1). In cases with a short latency period, rash, fever and eosinophilia are common and the onset is typically abrupt and severe, and recovery is rapid. In cases with a longer latency (Case 2), the onset is more typically insidious, liver biopsy may resemble chronic hepatitis and demonstrate fibrosis, and autoantibodies are often present. The late form of hepatitis may also accompany the lupus-like syndrome that occurs with hydralazine, particularly in high doses when given for 6 months or more. Recovery can be prolonged. Autoantibodies to isoforms of the P450 system (CYP 1A2) have been identified in patients with hepatotoxicity due to the structurally related antihypertensive agent dihydralazine (available in Europe, but not the United States) and which is associated with a higher rate of hepatotoxicity than hydralazine.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：肼苯哒嗪

Compound:hydralazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服肼苯哒嗪时与食物同服可以提高药物的生物利用度。静脉注射0.3mg/kg的剂量会导致曲线下面积(AUC)为17.5-29.4µM·min，而口服1mg/kg的剂量则导致AUC为4.0-30.4µM·min。口服肼苯哒嗪的Cmax（最大血药浓度）为0.12-1.31µM，这取决于患者的乙酰化状态。

Taking oral hydralazine with food improves the bioavailability of the drug. An intravenous dose of 0.3mg/kg leads to an AUC of 17.5-29.4µM\*min and a 1mg/kg oral dose leads to an AUC of 4.0-30.4µM\*min. The Cmax of oral hydralazine is 0.12-1.31µM depending on the acetylator status of patients.

来源:DrugBank

吸收、分配和排泄

• 消除途径

10%的肼屈嗪在粪便中回收；65-90%在尿液中回收。

<10% of hydralazine is recovered in the feces; 65-90% is recovered in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

充血性心力衰竭患者的分布容积为1.34±0.79L/kg，高血压患者的分布容积为1.98±0.22L/kg。

The volume of distribution is 1.34±0.79L/kg in congestive heart failure patients and 1.98±0.22L/kg in hypertensive patients.

来源:DrugBank

吸收、分配和排泄

• 清除

大多数肼屈嗪的清除是在肝脏外进行的-快速乙酰化者的清除率为55%，慢速乙酰化者为70%。充血性心力衰竭患者的平均清除率为1.77±0.48L/kg/h，而高血压患者的平均清除率为42.7±8.9mL/min/kg。

The majority of hydralazine clearance is extrahepatic- 55% for rapid acetylators and 70% for slow acetylators. The average clearance in congestive heart failure patients is 1.77±0.48L/kg/h, while hypertensive patients have an average clearance of 42.7±8.9mL/min/kg.

来源:DrugBank