Chlordiazepoxide | 58-25-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: Chlordiazepoxide
• 英文别名: 7-chloro-4-hydroxy-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine
• CAS: 58-25-3
• 化学式: C₁₆H₁₄ClN₃O
• 分子量: 299.75
• InChiKey: BUCORZSTKDOEKQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  48.2
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

在人和狗中，生物转化导致2位甲基氨基取代基的连续水解和产生的内酰胺的水解裂解；7-氯-1,3-二氢-5-苯基-2H-1,4-苯并二氮杂-2-酮-4-氧化物和N-(2-氨基-5-氯-α-苯基苄基)甘氨酸-N-氧化物被排出在尿液中。

IN MAN & DOGS, BIOTRANSFORMATION RESULTS IN SUCCESSIVE HYDROLYSIS OF METHYLAMINO-SUBSTITUENT IN 2-POSITION & HYDROLYTIC FISSION OF RESULTANT LACTAM; 7-CHLORO-1,3-DIHYDRO-5-PHENYL-2H-1,4-BENZODIAZEPINE-2-ONE-4-OXIDE & N-(2-AMINO-5-CHLORO-ALPHA-PHENYL-BENZYLIDENE) GLYCINE-N-OXIDE ARE EXCRETED IN URINE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在狗身上，利必通的1%剂量在尿液中以氧杂蒽酸葡萄糖苷酸的形式发现，另外1%在粪便中以自由的氧杂蒽酸葡萄糖苷酸形式存在。这些次要代谢物可能是通过内酰胺经过涉及N-氧化物功能还原的步骤产生的。

IN DOGS, 1% OF A DOSE OF LIBRIUM FOUND IN URINE AS OXAZEPAM GLUCURONIDE AND A FURTHER 1% IN FECES AS FREE OXAZEPAM GLUCURONIDE. THESE MINOR METABOLITES PRESUMABLY ARISE VIA LACTAM BY STEPS INVOLVING REDUCTION OF N-OXIDE FUNCTION.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在人体和猴子中产生2-氨基-7-氯-5-苯基-3H-1,4-苯并二氮杂-4-氧化物。/根据表格/

YIELDS 2-AMINO-7-CHLORO-5-PHENYL-3H-1,4-BENZODIAZEPINE-4-OXIDE IN MAN, IN MONKEY. /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在假单胞菌中产生N-(2-氨基-5-氯-α-苯基苄基亚胺)-甘氨酸-N-氧化物，在梭菌中也如此。/来自表格/

YIELDS N-(2-AMINO-5-CHLORO-ALPHA-PHENYLBENZYLIDENE)-GLYCINE-N-OXIDE IN PSEUDOMONAS, IN CLOSTRIDIUM. /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

氯化二氮卓与中枢神经系统内的几个位点上的GABA(A)受体复合物的立体特异性苯二氮卓（BZD）结合位点结合，包括边缘系统和网状结构。这导致抑制性神经递质GABA与GABA(A)受体的结合增加。因此，BZDs增强通过GABA受体通道的GABA介导的氯离子流入，导致膜超极化。净神经抑制效应产生了观察到的镇静、催眠、抗焦虑和肌肉松弛特性。

Chlordiazepoxide binds to stereospecific benzodiazepine (BZD) binding sites on GABA (A) receptor complexes at several sites within the central nervous system, including the limbic system and reticular formation. This results in an increased binding of the inhibitory neurotransmitter GABA to the GABA(A) receptor.BZDs, therefore, enhance GABA-mediated chloride influx through GABA receptor channels, causing membrane hyperpolarization. The net neuro-inhibitory effects result in the observed sedative, hypnotic, anxiolytic, and muscle relaxant properties.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

氯氮卓与其他苯二氮卓类药物一样，很少与血清ALT升高有关，临床上因其使用而引起的明显肝损伤也很少见。至少有十份关于氯氮卓引起急性肝损伤的病例报告，这些报告大多发表于1980年之前。急性肝损伤发病的潜伏期为1到4个月，肝酶升高的模式从肝细胞型到胆汁淤积型和混合型不等。损伤通常是轻到中度的，并且是自限性的。发热和皮疹是不常见的，自身抗体的形成也不常见。

Chlordiazepoxide, as with other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from its use is rare. There have been at least ten case reports of acute liver injury from chlordiazepoxide, published largely before 1980. The latency to onset of acute liver injury was 1 to 4 months, and the pattern of liver enzyme elevations varied from hepatocellular to cholestatic and mixed. The injury was usually mild-to-moderate in severity and self-limited. Fever and rash were uncommon, as was autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：氯氮卓

Compound:chlordiazepoxide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：5

Severity Grade:5

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 排除途径

氯氮卓通过尿液排出，其中1%至2%未发生改变，3%至6%以结合物形式存在。

Chlordiazepoxide is excreted in the urine, with 1% to 2% unchanged and 3% to 6% as conjugate.

来源:DrugBank

吸收、分配和排泄

INCR DISAPPEARANCE RATES OF CHLORDIAZEPOXIDE & ITS METABOLITES WERE OBSERVED AFTER SINGLE PRETREATMENT DOSE TO MICE. INCR CLEARANCE WAS INSUFFICIENT TO EXPLAIN TOLERANCE OBSERVED AND THE POSSIBILITY OF ALTERED DRUG DISTRIBUTION BETWEEN BLOOD & BRAIN TISSUE CANNOT BE EXCLUDED. 氯氮卓及其代谢物在小鼠单次预处理剂量后的消失速率增加。增加的清除率不足以解释观察到的耐受性，不能排除药物在血液和脑组织之间分布改变的可能性。

INCR DISAPPEARANCE RATES OF CHLORDIAZEPOXIDE & ITS METABOLITES WERE OBSERVED AFTER SINGLE PRETREATMENT DOSE TO MICE. INCR CLEARANCE WAS INSUFFICIENT TO EXPLAIN TOLERANCE OBSERVED AND THE POSSIBILITY OF ALTERED DRUG DISTRIBUTION BETWEEN BLOOD & BRAIN TISSUE CANNOT BE EXCLUDED.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

给药后2-6小时，口服氯氮卓的猕猴组织中(14)C水平最高。大脑与血液中(14)C的浓度比大于1。肝脏和肾脏中(14)C的浓度最高，心脏、肺、脾、大脑、肾上腺、胰腺和脂肪中较低。24小时后，消化道含有15%，组织中33%，尿液中34%，粪便中1%。

LEVELS OF (14)C WERE MAX IN TISSUES OF CYNOMOLGUS MONKEYS 2-6 HR AFTER ORAL DOSE OF CHLORDIAZEPOXIDE. BRAIN TO BLOOD CONCN RATIOS OF (14)C WERE GREATER THAN 1. CONCN OF (14)C WERE HIGHEST IN LIVER & KIDNEYS & LOWER IN HEART, LUNGS, SPLEEN, BRAIN, ADRENALS, PANCREAS & FAT. AFTER 24 HR, GI TRACT CONTAINED 15%, TISSUES 33%, URINE 34%, & FECES 1%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氯氮卓通过口服比肌肉注射吸收更快且更可预测，但个体之间的血药浓度差异很大。

Chlordiazepoxide is absorbed more rapidly and predictably after oral than after intramuscular administration, but blood levels vary widely among individuals.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氯硝西泮的血浆浓度-时间曲线可以通过双指数表达式满意地描述，这与静脉给药于健康男性志愿者后的双室模型系统一致。分布相和消除相的平均半衰期分别为0.25小时和9.4小时，而中央室（V1）和整体分布（Vdbeta）的平均体积分别为体重的18%和31%。从肌肉注射剂量中吸收药物相对较慢，为了充分描述氯硝西泮的血浆水平，需要纳入一个双室“肌肉模型”，包括在肌肉组织中沉淀和溶解的药物。氯硝西泮的分布体积在女性受试者中显著大于男性，这表明女性体内的药物分布更为广泛。氯硝西泮仅在一定程度上被红细胞摄取。

PLASMA CONCENTRATION-TIME CURVES OF CHLORDIAZEPOXIDE WERE SATISFACTORILY DESCRIBED BY A BI-EXPONENTIAL EXPRESSION CONSISTENT WITH A TWO-COMPARTMENT MODEL SYSTEM AFTER INTRAVENOUS DOSES TO HEALTHY MALE VOLUNTEERS. MEAN HALF-LIFE VALUES OF THE DISTRIBUTION AND ELIMINATION PHASE WERE 0.25 AND 9.4 HOURS, RESPECTIVELY, WHILE MEAN VALUES FOR VOLUMES OF THE CENTRAL COMPARTMENT (V1) AND THE OVERALL DISTRIBUTION (VDBETA) WERE 18 AND 31% OF BODY WEIGHT. DRUG ABSORPTION FROM IM DOSES WAS COMPARATIVELY SLOW AND ADEQUATE DESCRIPTION OF RESULTING PLASMA LEVELS OF CHLORDIAZEPOXIDE REQUIRED THE INCORPORATION OF A TWO-COMPARTMENT "MUSCLE MODEL" WHICH INCLUDED PRECIPITATED AND SOLUBILIZED DRUG IN MUSCLE TISSUE. DISTRIBUTION VOLUMES OF CHLORDIAZEPOXIDE WERE SIGNIFICANTLY LARGER IN FEMALE SUBJECTS THAN IN THE MALES, SUGGESTING MORE EXTENSIVE DRUG DISTRIBUTION AMONG FEMALES. CHLORDIAZEPOXIDE IS TAKEN UP BY THE RED CELLS TO ONLY A LIMITED EXTENT.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

制备方法

将2-氨基-5-氯二苯酮与相应的试剂反应，得到2-氨基-5-氯二苯酮肟，再经环合、扩环而得。粗品用乙醇重结晶，活性炭脱色，即得成品。

用途简介

本品为弱安定药，具有镇静、抗焦虑、抗惊厥及肌肉松弛作用。主要用于治疗焦虑症、强迫性神经官能症、神经衰弱失眠及高血压等。与其他抗癫痫药合用可抑制癫痫大发作或小发作。长期大量服用可成瘾。

用途

本品为弱安定药，具有镇静、抗焦虑、抗惊厥及肌肉松弛作用。主要用于治疗焦虑症、强迫性神经官能症、神经衰弱失眠及高血压等。与其他抗癫痫药合用可抑制癫痫大发作或小发作。长期大量服用可成瘾。