Kappadione | 131-13-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: Kappadione
• 英文别名: tetrasodium;(2-methyl-4-phosphonatooxynaphthalen-1-yl) phosphate
• CAS: 131-13-5
• 化学式: C11H8Na4O8P2
• 分子量: 422.08
• InChiKey: GZBACHSOZNEZOG-UHFFFAOYSA-J

计算性质

• 辛醇/水分配系数(LogP)：
  -12.42
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  145
• 氢给体数：
  0
• 氢受体数：
  8

ADMET

代谢

水溶性维生素K或2-甲基-1,4-萘醌是一种合成维生素K类似物，通过微粒体NADPH-细胞色素P450还原酶和线粒体NADH-泛醌氧化还原酶（复合物I）等酶的作用下进行一电子还原，导致氧化还原循环，或者通过NAD(P)H-醌氧化还原酶进行两电子还原而解毒。维生素K是一组脂溶性、疏水性的维生素，自然存在两种形式（以及3种合成形式）：维生素K1，存在于植物中，和维生素K2，由细菌合成。维生素K是重要的饮食成分，因为它作为辅因子在激活维生素K依赖性蛋白质中是必需的。维生素K的代谢主要发生在肝脏。在第一步中，维生素K通过NADPH脱氢酶等醌还原酶还原为其醌形式。还原型维生素K是转化维生素K依赖性蛋白前体到其活性状态所需的形态。它作为膜整合酶维生素K依赖性γ-羧化酶（以及水和二氧化碳作为共底物）的辅因子，该羧化酶将谷氨酸残基羧化为某些蛋白质上的γ-羧基-谷氨酸残基，从而激活它们。每个转化的谷氨酸残基产生一个维生素K环氧化物分子，某些蛋白质可能有一个以上的残基需要羧化。为了结束循环，维生素K环氧化物通过维生素K环氧化物还原酶酶返回到维生素K，这也是一种膜整合蛋白。维生素K依赖性蛋白质包括各种重要的凝血因子，如凝血酶原。华法林和其他香豆素类药物通过阻断维生素K环氧化物还原酶起到抗凝作用。

Menadione or 2-methyl-1,4-naphthoquinone is a synthetic vitamin K analog, undergoes 1-electron reduction by enzymes such as microsomal NADPH–cytochrome P450 reductase and mitochondrial NADH–ubiquinone oxidoreductase (complex I), resulting in redox cycling, or it detoxification via two-electron reduction by NAD(P)H–quinone oxidoreductase. Vitamin K is a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and in 3 synthetic forms): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofactor in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NADPH dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To end the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include various important coagulation factors, such as prothrombin. Warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase.

来源:DrugBank

吸收、分配和排泄

• 吸收

水溶性维生素K的合成类似物，建议在肠道吸收不良或胆汁流量不足的情况下使用。主要的缺点是它需要24小时才能开始治疗效果，然而，这种效果可以持续数天。剂量为每日口服5-40毫克。即使在中等剂量下，磷酸钠也可能导致溶血性贫血，因此新生儿不应接受这种药物。这种预防措施特别适用于那些缺乏葡萄糖6-磷酸脱氢酶（G6PD）的人；他们不成熟肝脏无法补偿重胆红素负荷，并且有增加核黄疸的风险。

Menadiol sodium phosphate (vitamin K3), the synthetic analog of vitamin K, being water soluble, is advised in intestinal malabsorption or in states in which bile flow is deficient. The primary disadvantage is that it takes 24 h to initiate therapeutic effects, however, this effect lasts for several days. The dose is 5–40 mg orally, daily. Menadiol sodium phosphate, even in moderate doses, may lead to hemolytic anemia and, for this reason, neonates should not receive this medication. This precautionary measure is valid especially those that are deficient in glucose 6-phosphate dehydrogenase (G6PD); their immature livers are unable to compensate for the heavy bilirubin load and there is an increased risk of kernicterus.

来源:DrugBank

吸收、分配和排泄

• 消除途径

维生素K在肝脏中大量代谢，并通过尿液和胆汁排出体外。在示踪剂研究中发现，大约20%的叶绿素酮（维生素K代谢物）注射剂量在尿液中找到，而大约40-50%通过胆汁系统随粪便排出。无论注射剂量是1毫克还是45微克，药物排出的比例是相同的。因此，可以推断，从每顿含有维生素K的餐中吸收的叶绿素酮的大约60-70%将通过排泄而丧失。已经鉴定出两种主要的人类排泄产物：具有5和7个碳侧链的羧酸，它们以葡萄糖苷酸结合物的形式通过尿液排出。胆汁代谢物尚未明确鉴定，但最初以水溶性结合物的形式排出，在通过肠道的过程中变为脂溶性，可能是通过肠道菌群的去结合作用。没有证据表明维生素K的体内储存是通过肠肝循环来维持的。维生素K本身过于亲脂性，无法通过胆汁排出，而侧链缩短的羧酸代谢物不具有生物活性。

Vitamin K is heavily metabolized in the liver and excreted in the urine and bile. In tracer studies, it was found that approximately 20% of an injected dose of phylloquinone (Vitamin K metabolite) was found in the urine whereas about 40-50 % was excreted in the feces via the biliary system. The proportion of drug excreted was the same regardless of whether the injected dose was 1 mg or 45 µg. It can, therefore, be inferred that about 60-70% percent of the amounts of phylloquinone absorbed from each vitamin-K containing meal will be lost to the body by excretion. Two major human excretion products have been identified: carboxylic acids with 5 and 7-carbon sidechains that are excreted in the urine as glucuronide conjugates. The biliary metabolites have not been clearly identified but are initially excreted as water-soluble conjugates and become lipid soluble during their passage through the gut, probably through deconjugation by the gut flora. There is no evidence for body stores of vitamin K being conserved by an enterohepatic circulation. Vitamin K itself is too lipophilic to be excreted in the bile and the sidechain-shortened carboxylic acid metabolites are not biologically active.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在对兔子的研究中，血浆中表观分布容积（V(d)/F）为30.833 ± 12.835升。

In a study of rabbits, the apparent volume of distribution (V(d)/F) in plasma was 30.833 ± 12.835 L.

来源:DrugBank

吸收、分配和排泄

• 清除

VK3的血浆清除率（CL/F）为0.822 ± 0.254 L min-1。

The plasma clearance (CL/F) of VK3 was 0.822 ± 0.254 L min-1. [LI572]

来源:DrugBank