Axion | 13422-51-0

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四吡咯及其衍生物
• 英文名称: Axion
• 英文别名: cobalt(2+);[(2R,5S)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 1-[3-[(2R,3R,4Z,7S,9Z,12S,13S,14Z,17S,18S,19R)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7,12,17-tetrahydro-1H-corrin-21-id-3-yl]propanoylamino]propan-2-yl phosphate;hydrate
• CAS: 13422-51-0
• 化学式: C62H90CoN13O15P
• 分子量: 1347.4
• InChiKey: DQOCFCZRZOAIBN-JLKASCPDSA-L

物化性质

• 熔点：
  >300 °C
• 溶解度：
  甲醇：10 mg/mLat 20 °C，澄清，暗红色
• LogP：
  -2.812 (est)
• 颜色/状态：
  Dark red, orthorhombic needles or platelets from water and acetone
• 气味：
  ODORLESS OR HAS NOT MORE THAN SLIGHT ACETONE ODOR
• 蒸汽压力：
  2.06X10-11 mm Hg at 25 °C

计算性质

• 辛醇/水分配系数(LogP)：
  2.49
• 重原子数：
  92
• 可旋转键数：
  16
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  453
• 氢给体数：
  10
• 氢受体数：
  20

ADMET

代谢

羟钴胺素的毒物动力学在大鼠和犬类单次给药后进行了研究。在犬类中，自由钴胺素-(III)和总钴胺素-(III)的药时曲线下面积（AUC）与剂量成正比增加。自由钴胺素-(III)和总钴胺素-(III)的平均最大浓度（Cmax）是人类接受5.0和10.0克羟钴胺素治疗时的1到5倍。犬类中自由钴胺素-(III)和总钴胺素-(III)的终末半衰期分别达到大约6和8小时。大鼠中的相应数字分别为3和5小时。在犬类中，总钴胺素-(III)的清除率（0.064至0.083 L/h/kg）是自由钴胺素-(III)清除率的6-7倍。

Toxicokinetics of hydroxocobalamin were studied in rats and in dogs after single administration. In dogs, the AUCs of free cobalamins-(III) and total cobalamins-(III) increased proportionally to the dose. Mean Cmax measured for free- and total cobalamins-(III) were 1 to 5 fold higher than those measured in humans treated with 5.0 and 10.0 g hydroxocobalamin. Terminal half-lives reached approximately 6 and 8 hours for free and total cobalamins-(III), respectively in dogs. Corresponding figures in rats amounted to 3 and 5 hours. In dogs, the clearance of total cobalamins-(III) (0.064 to 0.083 L/h/kg) was 6-7 fold lower than clearance of free cobalamins-(III).

来源:Hazardous Substances Data Bank (HSDB)

代谢

羟钴胺与蛋白质的结合可以被认为是可逆的代谢。羟钴胺还会与氰化物反应，从而形成氰钴胺。这个复合物非常稳定，因此被认为是羟钴胺的生理终产物，尤其是在氰化物中毒期间。

The binding of hydroxocobalamin to proteins may be regarded as reversible metabolism. Hydroxocobalamin also reacts with cyanide thereby forming cyanocobalamin. This complex is highly stable and is therefore regarded as a physiological end product of hydroxocobalamin especially during cyanide intoxication.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

据报道，氯霉素与维生素B12的联合使用可能会拮抗维生素B12在维生素B12缺乏患者中对造血的响应。在接受这两种药物的患者中，应对维生素B12的血液学反应进行仔细监测，并应考虑使用其他抗感染药物。/维生素B12/

Concurrent administration of chloramphenicol and vitamin B12 reportedly may antagonize the hematopoietic response to vitamin B12 in vitamin B12-deficient patients. The hematologic response to vitamin B12 in patients receiving both drugs should be carefully monitored and alternate anti-infectives should be considered. /Vitamin B12/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

泼尼松在少数患有恶性贫血的患者中已被报告能增加维生素B12的吸收和内因子（IF）的分泌，但在部分或全部胃切除的患者中则没有这种现象。这些发现的临床重要性尚不清楚。/维生素B12/

Prednisone has been reported to increase the absorption of vitamin B12 and secretion of intrinsic factor (IF) in a few patients with pernicious anemia, but not in patients with partial or total gastrectomy. The clinical importance of these findings is unknown. /Vitamin B12/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维生素C可能会在体外破坏大量的膳食维生素B12；当摄入大剂量的维生素C，并且与口服维生素B12的服用时间相隔不超过1小时时，应考虑这种可能性。/维生素B12/

Ascorbic acid may destroy substantial amounts of dietary vitamin B12 in vitro; this possibility should be considered when large doses of ascorbic acid are ingested within 1 hour of oral vitamin B12 administration. /Vitamin B12/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

从胃肠道吸收维生素B12可能会因氨基糖苷类抗生素、秋水仙碱、缓释钾制剂、氨基水杨酸及其盐类、抗惊厥药（例如：苯妥英、苯巴比妥、普里米酮）、小肠钴照射以及超过两周的过量饮酒而降低。同时使用秋水仙碱可能会增加新霉素引起的维生素B12吸收不良。/维生素B12

Absorption of vitamin B12 from the GI tract may be decreased by aminoglycoside antibiotics, colchicine, extended-release potassium preparations, aminosalicylic acid and its salts, anticonvulsants (e.g., phenytoin, phenobarbital, primidone), cobalt irradiation of the small bowel, and by excessive alcohol intake lasting longer than 2 weeks. Neomycin-induced malabsorption of vitamin B12 may be increased by concurrent administration of colchicine. /Vitamin B12

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在同时使用Cyanokit和其他氰化物解毒剂时应谨慎，因为尚未确立共同给药的安全性。如果决定在使用Cyanokit的同时给予另一种氰化物解毒剂，这些药物不应在同一静脉输液管路中同时给药。

Caution should be exercised when administering other cyanide antidotes simultaneously with Cyanokit, as the safety of coadministration has not been established. If a decision is made to administer another cyanide antidote with Cyanokit, these drugs should not be administered concurrently in the same IV line.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠中进行了一项研究，调查了经鼻腔给药后羟钴胺从鼻腔直接运输到脑脊液的可能性，并将结果与人类研究进行了比较。羟钴胺通过使用血管通路端口（VAP）同时以鼻腔（214微克/大鼠）和颈静脉（49.5微克/大鼠）给药给大鼠（n=8）。在药物给药前后，采集了血液和脑脊液样本，并通过放射免疫分析法进行分析。鼻腔给药后脑脊液/血浆的AUC比值与静脉输注后的比值没有差异，这表明羟钴胺通过血液循环穿过血脑屏障（BBB）进入脑脊液。这一相同的运输路线在大鼠和比较人类研究中通过脑脊液和血浆的累积AUC-时间剖面得到证实，显示出羟钴胺在血浆吸收和脑脊液摄取之间存在30分钟的延迟。目前在大鼠中的结果表明，与静脉给药相比，经鼻腔给药后脑脊液中没有额外的羟钴胺摄取，这与人类研究中发现的结果一致。

The possibility of direct transport of hydroxocobalamin from the nasal cavity into the cerebrospinal fluid after nasal administration in rats was investigated and the results were compared with a human study. Hydroxocobalamin was given to rats (n=8) both intranasally (214 ug/rat) and intravenously (49.5 ug/rat) into the jugular vein using a Vascular Access Port (VAP). Prior to and after drug administration, blood and cerebrospinal fluid samples were taken and analysed by radioimmunoassay. The AUCcerebrospinal fluid/AUCplasma ratio after nasal delivery does not differ from the ratio after intravenous infusion, indicating that hydroxocobalamin enters the cerebrospinal fluid via the blood circulation across the blood-brain barrier (BBB). This same transport route is confirmed by the cumulative AUC-time profiles in cerebrospinal fluid and plasma, demonstrating a 30 min delay between plasma absorption and cerebrospinal fluid uptake of hydroxocobalamin in rats and in a comparative human study. The present results in rats show that there is no additional uptake of hydroxocobalamin in the cerebrospinal fluid after nasal delivery compared to intravenous administration, which is in accordance with the results found in humans.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

50%的氢氧钴胺素剂量在2.5小时内从注射部位消失。氢氧钴胺素与血浆蛋白结合并在肝脏中储存。它通过胆汁排出，并经历一些肠肝循环。在注射500到1000微克氢氧钴胺素后的72小时内，16%到66%的注射剂量可能会出现在尿液中。大部分在最初的24小时内排出。

Fifty percent of the administered dose of hydroxocobalamin disappears from the injection site in 2.5 hours. Hydroxocobalamin is bound to plasma proteins and stored in the liver. It is excreted in the bile and undergoes some enterohepatic recycling. Within 72 hours after injection of 500 to 1000 mcg of hydroxocobalamin, 16 to 66 percent of the injected dose may appear in the urine. The major portion is excreted within the first 24 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

羟钴胺素从注射部位的吸收速度比氰钴胺素慢，并且有证据表明羟钴胺素在肝脏的摄取可能大于氰钴胺素。人们认为，与氰钴胺素相比，羟钴胺素在血液和组织中的特定和非特异性结合蛋白的亲和力更强，以及从注射部位吸收更慢，这导致了羟钴胺素较氰钴胺素有更高的保留率。

Hydroxocobalamin is absorbed more slowly from the site of injection than is cyanocobalamin and there is some evidence that liver uptake of hydroxocobalamin may be greater than that of cyanocobalamin. It is believed that the increased retention of hydroxocobalamin compared with that of cyanocobalamin results from the greater affinity of hydroxocobalamin for both specific and nonspecific binding proteins in blood and tissues, as well as to its slower absorption from the injection site.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在胃酸和胰腺蛋白水解酶的作用下，饮食中的维生素B12从食物和唾液结合蛋白中释放出来，并与胃内源因子结合。当维生素B12-内源因子复合物到达回肠时，它与粘膜细胞表面的受体相互作用，并主动转运进入循环。充足的内在因子、胆汁和碳酸氢钠（以提供适宜的pH值）都是回肠转运维生素B12所必需的。成年人维生素B12缺乏很少是因为饮食本身不足；相反，它通常反映出这一复杂吸收序列的一个或另一个方面的缺陷。胃酸缺乏和由于胃萎缩或胃手术导致的壁细胞内源因子分泌减少是成年人维生素B12缺乏的常见原因。对抗壁细胞或内源因子复合物的抗体也可能在产生缺乏症中发挥重要作用。许多肠道疾病都可能干扰吸收，包括胰腺疾病（胰腺蛋白水解酶分泌丧失）、细菌过度生长、肠道寄生虫、乳糜泻以及疾病或手术导致的回肠粘膜细胞局部损伤。/维生素B-12/

In the presence of gastric acid and pancreatic proteases, dietary vitamin B12 is released from food and salivary binding protein and bound to gastric intrinsic factor. When the vitamin B12-intrinsic factor complex reaches the ileum, it interacts with a receptor on the mucosal cell surface and is actively transported into circulation. Adequate intrinsic factor, bile, and sodium bicarbonate (to provide a suitable pH) all are required for ileal transport of vitamin B12. Vitamin B12 deficiency in adults is rarely the result of a deficient diet per se; rather, it usually reflects a defect in one or another aspect of this complex sequence of absorption. Achlorhydria and decreased secretion of intrinsic factor by parietal cells secondary to gastric atrophy or gastric surgery is a common cause of vitamin B12 deficiency in adults. Antibodies to parietal cells or intrinsic factor complex also can play a prominent role in producing a deficiency. A number of intestinal diseases can interfere with absorption, including pancreatic disorders (loss of pancreatic protease secretion), bacterial overgrowth, intestinal parasites, sprue, and localized damage to ileal mucosal cells by disease or as a result of surgery. /Vitamin B-12/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 危险品运输编号：
  NONH for all modes of transport

制备方法与用途

用途

羟钴胺素是合成硝基钴胺素和醋酸钴胺素的重要中间体，并且也是维生素B12的一种生理类似物，其中CN基团被OH取代。在水溶液中，它以羟基异构体和离子水异构体（aquacobalamin）的平衡混合物形式存在。此外，羟钴胺素还是辅酶甲基钴胺素及钴胺素的前体，并且具有配位化合物的特性。

作为一种维生素，羟钴胺素对造血有重要作用。

概述

注射用羟钴胺是一种安全无毒、迅速起效的新一代氰化物解毒剂，商品名为Cyanokit。该产品由法国EMD制药公司生产并提供原料，而美国DeyLaboratories公司则负责包装和销售。

这种药物主要用于治疗恶性贫血及其他因缺乏维生素B12引起的病症。在大剂量使用时，它还可以作为氰化物的解毒剂，将氰化物转化为无害的氰钴胺。