苯巴比妥 | 50-06-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 苯巴比妥
• 中文别名: 鲁米那；5-乙基-5-苯基-1-甲基-2,4,6-(1H,3H,5H)-嘧啶三酮；苯巴比通
• 英文名称: phenobarbital
• 英文别名: 5-ethyl-5-phenylbarbituric acid；5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione
• CAS: 50-06-6
• 化学式: C₁₂H₁₂N₂O₃
• 分子量: 232.239
• InChiKey: DDBREPKUVSBGFI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  75.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

肝脏（主要是通过CYP2C19）。

Hepatic (mostly via CYP2C19).

来源:DrugBank

代谢

苯巴比妥被肝脏羟基化，形成p-羟基苯巴比妥，这是一种无活性的代谢物。苯巴比妥是诱导其他药物代谢酶的强效物质，但没有确凿的证据表明苯巴比妥加速了其自身的代谢。

Phenobarbital is hydroxylated by the liver to form p-hydroxyphenobarbital, an inactive metabolite. Phenobarbital is a potent inducer of the enzymes involved in the metabolism of other drugs, but there is no conclusive evidence that phenobarbital accelerates its own metabolism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

巴比妥类药物的不活跃代谢物以葡萄糖醛酸的结合物形式被排出体外。

The inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid.

来源:Hazardous Substances Data Bank (HSDB)

代谢

生物转化主要发生在肝脏的微粒体酶系统中。/巴比妥类药物/

Biotransformation occurs primarily by the hepatic microsomal enzyme system. /Barbiturates/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠和豚鼠中产生的苯巴比妥钠的代谢物包括：5-(3,4-二羟基-1,5-环己二烯-1-基)-5-乙基巴比妥酸；5-(1-羟基乙基)-5-苯基巴比妥酸；5-(3,4-二羟基苯基)-5-乙基巴比妥酸；以及5-(4-羟基苯基)-5-乙基巴比妥酸...

Metabolites of phenobarbital sodium produced in rats and guinea pigs are 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-ethylbarbituric acid; 5-(1-hydroxyethyl)-5-phenylbarbituric acid; 5-(3,4-dihydroxyphenyl)-5-ethylbarbituric acid; and 5-(4-hydroxyphenyl)-5-ethylbarbituric acid ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

苯巴比妥作用于GABAA受体，增加突触抑制。这提高了癫痫发作的阈值，并减少了从癫痫灶传播的癫痫活动。苯巴比妥还可能抑制钙通道，导致兴奋性递质释放减少。苯巴比妥的镇静催眠效果可能是其对控制中枢神经系统觉醒的多突触中脑网状结构作用的结果。

Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

前瞻性研究表明，长期使用苯巴比妥治疗的受试者中，不到1%的人血清转氨酶水平会升高。临床上明显的苯巴比妥肝毒性很少见，但一旦发生可能迅速出现，且严重甚至致命。苯巴比妥肝毒性通常发生在抗惊厥药物超敏反应综合征的背景下，表现为发热、皮疹、面部水肿、淋巴结病、白细胞计数升高和嗜酸性粒细胞增多，这些症状通常在开始治疗后的1周到几个月内出现。肝脏受累很常见，但通常轻微且不伴有黄疸，并且被超敏反应的其他特征（皮疹、发热）所掩盖。在某些情况下，肝脏受累更为明显，表现为血清酶水平显著升高、黄疸甚至出现肝功能衰竭的迹象。血清酶升高的典型模式是混合型的，但也可能是肝细胞型或胆汁淤积型的。肝脏活检显示混合性肝炎-胆汁淤积损伤，伴有嗜酸性粒细胞的显著增多和偶尔的肉芽肿。重新接触通常会导致复发，应当避免。

Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term phenobarbital therapy. Clinically apparent hepatotoxicity from phenobarbital is rare but can be abrupt in onset, severe and even fatal. Phenobarbital hepatotoxicity typically occurs in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia occurring 1 week to several months after starting therapy. Liver involvement is common, but is usually mild and anicteric and overshadowed by other features of hypersensitivity (rash, fever). In some cases, hepatic involvement is more prominent with marked elevations in serum enzyme levels, jaundice and even signs of hepatic failure. The typical pattern of serum enzyme elevations is mixed, but can be hepatocellular or cholestatic. Liver biopsy shows mixed hepatitis-cholestatic injury with prominence of eosinophils and occasionally granulomata. Re-exposure usually results in recurrence and should be avoided.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：苯巴比妥

Compound:phenobarbital

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

吸收、分配和排泄

• 吸收

以口服、直肠或非肠道给药后不同程度地被吸收。盐类的吸收速度比酸类快。如果钠盐以稀释溶液形式摄入或者在空腹时服用，吸收速率会增加。

Absorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.

来源:DrugBank

吸收、分配和排泄

大约70-90%的苯巴比妥口服剂量会从胃肠道缓慢吸收。经肛门给药苯巴比妥钠后，药物很容易从结肠吸收。口服苯巴比妥后，血药浓度在8-12小时内达到峰值，脑内浓度在10-15小时内达到峰值。... 当静脉注射苯巴比妥钠时，通常在5分钟内开始起效，30分钟内达到最大效果。肌内注射或皮下给药苯巴比妥钠的起效时间稍慢。苯巴比妥钠经非肠道给药的作用持续时间通常是4-6小时。

About 70-90% of an oral dose of phenobarbital is absorbed slowly from the GI tract. Following rectal administration of phenobarbital sodium, the drug is readily absorbed from the colon. Following oral administration of phenobarbital, peak blood concentrations are reached in 8-12 hours and peak brain concentrations in 10-15 hours. ... When phenobarbital sodium is administered IV, the onset of action usually occurs within 5 minutes and maximum effects are achieved within 30 minutes. IM or subcutaneous administration of phenobarbital sodium results in a slightly slower onset of action. The duration of action of parenterally administered phenobarbital sodium is usually 4-6 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

巴比妥类药物在口服、直肠或肌肉注射后以不同程度被吸收。钠盐通过所有给药途径的吸收速度都比相应的酸快。当钠盐作为稀释溶液摄入或空腹服用时，口服吸收速率增加。酒精也提高了吸收速率，可能是通过增加通过胃粘膜的血流量。/巴比妥类药物概述/

Barbiturates are absorbed in varying degrees following oral, rectal, or im administration. The sodium salts are more rapidly absorbed by all routes of administration than are the acids. The rate of oral absorption is increased when the sodium salt is ingested as a dilute solution or taken on an empty stomach. Alcohol also enhances the rate of absorption, possibly by increasing blood flow through the gastric mucosa. /Barbiturates General Statement/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服或直肠给药后，作用开始时间因药物而异，戊巴比妥、异戊巴比妥、司可巴比妥和戊巴比妥的作用开始时间为10-30分钟，甲基苯巴比妥、美芬巴比妥和苯巴比妥的作用开始时间为20-60分钟。肌内注射给药会使作用开始时间稍微快一些。静脉注射阿莫巴比妥、戊巴比妥、苯巴比妥或司可巴比妥的钠盐后，作用开始时间从几乎立即到5分钟不等，其中甲己巴比妥、戊巴比妥和硫喷妥的作用几乎立即发生，而苯巴比妥需要5分钟。硫喷妥或戊巴比妥的最大效果可以在大约1分钟内达到，而苯巴比妥可能需要多达30分钟才能达到最大效果。/巴比妥类药物一般声明/

Following oral or rectal administration, the onset of action varies from 10-30 minutes for amobarbital, aprobarbital, butabarbital, pentobarbital, and secobarbital and from 20-60 minutes for metharbital, mephobarbital, and phenobarbital. IM administration results in a slightly faster onset of action. Following iv administration of the sodium salts of amobarbital, pentobarbital, phenobarbital, or secobarbital, the onset of action ranges from almost immediately for methohexital, pentobarbital, and thiopental to 5 minutes for phenobarbital. Maximum effects of thiopental or pentobarbital are achieved within about 1 minute while as much as 30 minutes may be required with administration of phenobarbital. /Barbiturates General Statement/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

所有巴比妥类药物的镇静效果持续时间通常为静脉注射后3-6小时，其他给药途径则为6-8小时。口服作为催眠药使用的巴比妥类药物之间催眠作用的持续时间似乎没有太大差异。因此，现在大多数权威机构认为应该根据巴比妥类药物预定的药理作用进行分类（即，镇静催眠巴比妥类药物和麻醉巴比妥类药物[戊巴比妥，硫喷妥钠（在美国已不再商业供应），硫戊巴比妥]），而不是按照长效（美沙比妥，美他比妥，苯巴比妥），中效（阿莫比妥和布他比妥），短效（阿普比妥，戊巴比妥和司可巴比妥），超短效（戊巴比妥，硫喷妥钠）来分类。/巴比妥类药物一般声明/

The duration of sedative effects of all the barbiturates is usually 3-6 hours following iv administration and 6-8 hours when the drugs are administered by other routes. There appears to be very little difference in duration of hypnotic action among barbiturates used orally as hypnotics. Therefore, most authorities now believe that barbiturates should be classified according to their intended pharmacologic action (ie, sedative-hypnotic barbiturates and anesthetic barbiturates [methohexital, thiamylal (no longer commercially available in the US), thiopental]), rather than as long-acting (mephobarbital, metharbital, and phenobarbital), intermediate-acting (amobarbital and butabarbital), short-acting (aprobarbital, pentobarbital, and secobarbital), and ultrashort-acting (methohexital, thiopental). /Barbiturates General Statement/

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

合成制备方法如下：

在醇钠的作用下，苯乙酸乙酯与草酸二乙酯发生缩合反应，再加热脱除CO₂，得到2-苯基丙二酸二乙酯；接着，在碱性条件下，该化合物与溴乙烷反应引入乙基，最后与脲进行缩合反应，从而制得目标产物。