(6R,7R)-7-[[(2E)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 80370-57-6

• 物质功能分类: 原料药 - 抗生素类药物 - 头孢菌素类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (6R,7R)-7-[[(2E)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
• 英文别名: (7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
• CAS: 80370-57-6
• 化学式: C₁₉H₁₇N₅O₇S₃
• 分子量: 523.6
• InChiKey: ZBHXIWJRIFEVQY-FITYNHDMSA-N

物化性质

• 熔点：
  >212°C (dec.)
• 密度：
  1.81±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO（轻微）、甲醇（非常轻微、加热、超声处理）
• 蒸汽压力：
  5.9X10-20 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 3.7 (carboxylic acid) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  256
• 氢给体数：
  3
• 氢受体数：
  13

ADMET

代谢

对4只雄性和4只雌性Sprague-Dawley大鼠肌肉注射(14)C-头孢噻呋(2 mg/kg体重)的研究发现，给药剂量的55%通过尿液排出，大约30%通过胃肠道和粪便排出。主要的尿代谢物是去戊酰头孢噻呋(DFC)。头孢噻呋在通过肌肉注射途径给药(14)C-头孢噻呋(2 mg/kg体重)的犊牛中的代谢情况相似。未代谢的头孢噻呋也存在于尿液中(总放射活性的4.4-21%)。

A study of 4 male and 4 female Sprague-Dawley rats treated intramuscularly with (14)C-ceftiofur (2 mg/kg bw) revealed that 55% of the administered dose was excreted in the urine and about 30% in the GI tract and faeces. The major urinary metabolite was desfuroylceftiofur (DFC). The metabolism of ceftiofur was similar in calves administered (14)C-ceftiofur (2 mg/kg bw) via the i.m. route. Unmetabolized ceftiofur was also present in the urine (4.4-21% of total radioactivity).

来源:Hazardous Substances Data Bank (HSDB)

代谢

在一项与牛进行的比较研究中，一组Sprague-Dawley大鼠（每性别7只）接受了单次口服剂量的(14)C-头孢噻呋（200 mg/kg体重）。大约55%的总剂量在尿液中回收，其余部分存在于粪便和胃肠道中。...主要的尿液代谢物是头孢噻呋磺氧基丙酸巯基酯。

A group of Sprague-Dawley rats (7/sex) received single oral doses of (14)C-ceftiofur (200 mg/kg bw) in a comparative study with calves. Approximately 55% of the total dose was recovered in the urine and the rest was present in the feces and GI tract. ... The major urinary metabolite was ceftiofursulfoxide cysteine thioester.

来源:Hazardous Substances Data Bank (HSDB)

代谢

高效液相色谱分析体外由aro氯诱导的大鼠肝脏S-9部分形成的(14)C-头孢噻呋代谢物显示，脱氧头孢噻呋是主要的代谢物。低剂量(119 mg/kg bw)的头孢噻呋在15分钟内被完全代谢。较高剂量(857 mg/kg bw)在孵化60分钟后转化为脱氧头孢噻呋。

HPLC analysis of metabolites of (14)C-ceftiofur formed by arochlor-induced rat liver S-9 fractions in vitro revealed that desfuroylceftiofur was the major metabolite. Low doses (119 mg/kg bw) of ceftiofur were completely metabolized within 15 minutes. Higher doses (857 mg/kg bw) were converted to desfuroylceftiofur after 60 minutes of incubation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在8周大的Sprague-Dawley大鼠（每性7只）中，通过口服灌胃给予（14）C-头孢噻呋（800 mg/kg体重/天），连续5天的研究发现了几个尿液代谢物，包括去戊酰头孢噻呋、头孢噻呋亚砜和胱氨酸二硫。

A study in 8-week old Sprague-Dawley rats (7/sex) treated with (14)C-ceftiofur (800 mg/kg bw/day) by oral gavage for 5 days revealed several urinary metabolites, including desfuroylceftiofur, ceftiofur sulfoxide, and cysteine disulfide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

对2只雄性大鼠进行了一项研究，这些大鼠接受了一次肌内注射(14)C-头孢噻呋，研究发现去甲酰头孢噻呋以与主要血清蛋白（白蛋白和α-1-抗胰蛋白酶）的巯基结合的复合物形式存在。

A study of 2 male rats treated with a single i.m. injection of (14)C-ceftiofur revealed that desfuroylceftiofur existed as complexes bound by sulfhydryl groups to major serum proteins, albumin and alpha-1- antitrypsin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。密切观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿...。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇...。监测心率和必要时治疗心律失常...。开始静脉输注5%葡萄糖水（D5W）/SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%盐水（NS）或乳酸钠林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象...。用地西泮或劳拉西泮治疗癫痫...。使用丙美卡因氢氯化物协助眼部冲洗...。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/在一项吸入研究中，头孢噻呋以8.3毫克/升的气溶胶浓度给药给5只雄性和5只雌性Sprague-Dawley大鼠，暴露时间为4小时。在暴露期间，大鼠表现出流涎、鼻涕和呼吸困难；这些症状在暴露后1小时内几乎消失。暴露后的症状包括6只大鼠腹泻，1只大鼠鼻孔周围有红色结痂物质。大体和显微镜检查没有发现任何与治疗相关的变化。[联合国粮农组织/世界卫生组织食品添加剂专家委员会；世界卫生组织食品添加剂系列36：某些兽药残留食品中毒理学评估：头孢噻呋（1996年）。截至2006年7月17日，可从以下网址获得：http://www.inchem.org/documents/jecfa/jecmono/v36je01.htm]

/LABORATORY ANIMALS: Acute Exposure/ In an inhalation study, ceftiofur was administered at an aerosol concentration of 8.3 mg/L to a group of 5 male and 5 female Sprague-Dawley rats for a 4-hr exposure period. During exposure, rats exhibited salivation, nasal discharge and dyspnea; these signs virtually disappeared within 1 hr after exposure. Post-exposure signs included diarrhea in 6 rats, and 1 rat exhibited a red encrusted material around the nares. Both gross and microscopic examination did not reveal any treatment-related changes.[Joint FAO/WHO Expert Committee on Food Additives; WHO Food Additive Series 36: Toxicological Evaluation of Certain Veterinary Drug Residues in Food: Ceftiofur (1996). Available from, as of July 17, 2006: http://www.inchem.org/documents/jecfa/jecmono/v36je01.htm]

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/在急性口服研究中，将头孢噻呋以单次剂量最高7800毫克/千克体重给药给Sprague-Dawley大鼠（每组10只/性别）。在两个最高剂量水平上观察到与治疗相关的腹泻。没有观察到其他与治疗相关的体征。[联合国粮农组织/世界卫生组织食品添加剂专家联合委员会；世界卫生组织食品添加剂系列36：某些兽药残留食品中毒理学的评估：头孢噻呋（1996年）。截至2006年7月17日，可从以下网址获得：http://www.inchem.org/documents/jecfa/jecmono/v36je01.htm]

/LABORATORY ANIMALS: Acute Exposure/ In an acute oral study, ceftiofur was administered as a single dose of up to 7800 mg/kg bw to groups of Sprague-Dawley rats (10/sex). Treatment-related diarrhea was noted at the 2 highest dose levels. No other treatment-related signs were observed.[Joint FAO/WHO Expert Committee on Food Additives; WHO Food Additive Series 36: Toxicological Evaluation of Certain Veterinary Drug Residues in Food: Ceftiofur (1996). Available from, as of July 17, 2006: http://www.inchem.org/documents/jecfa/jecmono/v36je01.htm]

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验动物：急性暴露/ 在对牛每天肌肉注射高达55毫克/千克体重/天，连续5天，以及对猪每天肌肉注射高达125毫克/千克体重/天，连续5天的研究中，最显著的发现是短暂的注射部位反应。[欧洲药品管理局（EMA），欧洲药品评估机构，兽药评估单位，兽药产品委员会；头孢噻夫，摘要报告（2）。EMA/MRL/498/98-最终（1999年7月）。截至2006年7月21日，可从以下网址获得：http://www.EMA.europa.eu/EMA/index.jsp?curl=pages/document_library/landing/document_library_search.jsp&murl=menus/document_library/document_library.jsp&mid]

/LABORATORY ANIMALS: Acute Exposure/ In studies in which cattle were given daily intramuscular injections of up to 55 mg/kg bw/day for 5 days and pigs were given dally intramuscular injections of up to 125 mg/kg bw/day for 5 days, transient injection site reactions were the most notable findings.[European Medicines Agency (EMEA), The European Agency for the Evaluation of Medicinal Products, Veterinary Medicines Evaluation Unit, Committee for Veterinary Medicinal Products; Ceftiofur, Summary Report (2). EMEA/MRL/498/98-Final (July 1999). Available from, as of July 21, 2006: http://www.ema.europa.eu/ema/index.jsp?curl=pages/document_library/landing/document_library_search.jsp&murl=menus/document_library/document_library.jsp&mid]

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

对4只雄性和4只雌性Sprague-Dawley大鼠肌肉注射(14)C-头孢噻呋（2毫克/千克体重）的研究发现，给药剂量的55%通过尿液排出，大约30%通过消化道和粪便排出。主要的尿液代谢物是脱氧酰头孢噻呋（DFC）。头孢噻呋在通过肌肉注射途径给予(14)C-头孢噻呋（2毫克/千克体重）的犊牛中的代谢情况相似。未代谢的头孢噻呋也出现在尿液中（总放射活性的4.4-21%）。

A study of 4 male and 4 female Sprague-Dawley rats treated intramuscularly with (14)C-ceftiofur (2 mg/kg bw) revealed that 55% of the administered dose was excreted in the urine and about 30% in the GI tract and feces. The major urinary metabolite was desfuroylceftiofur (DFC). The metabolism of ceftiofur was similar in calves administered (14)C-ceftiofur (2 mg/kg bw) via the i.m. route. Unmetabolized ceftiofur was also present in the urine (4.4-21% of total radioactivity).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项与牛进行的比较研究中，一组Sprague-Dawley大鼠（每性别7只）接受了单次口服剂量的(14)C-头孢噻呋（200 mg/kg体重）。大约55%的总剂量在尿液中回收，其余部分存在于粪便和胃肠道中。6小时时的血浆浓度为1 mg/kg，所有组织中都有微量的头孢噻呋残留（即肝、肌肉和脂肪）。肾脏中的残留水平最高，为0.7 mg/kg。

A group of Sprague-Dawley rats (7/sex) received single oral doses of (14)C-ceftiofur (200 mg/kg bw) in a comparative study with calves. Approximately 55% of the total dose was recovered in the urine and the rest was present in the feces and GI tract. Plasma concentration at 6 hr was 1 mg/kg and trace amounts of ceftiofur were present in all tissues (i.e. liver, muscle and fat). The highest residue levels (0.7 mg/kg) were present in kidney.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

一项对泌乳期奶牛使用(14)C-头孢噻呋（2.3 mg/kg 体重/天，连续5天）的研究发现，32-38%的放射性物质以自由代谢物的形式存在于牛奶中。主要的代谢物是脱脲基头孢噻呋半胱氨酸二硫化物，占总放射性的7-9%。牛奶中没有检测到母体化合物。

A study of lactating cows treated with (14)C-ceftiofur (2.3 mg/kg bw/day for 5 days) revealed that 32-38% of the radioactivity was present in the milk as free metabolites. The major metabolite was desfuroylceftiofur cysteine disulfide representing 7-9% of the total radioactivity. No parent compound was detected in the milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项对公牛进行的研究中，通过静脉注射(14)C-头孢噻呋，发现大约55%的给药剂量通过尿液排出，大约30%通过胃肠道和粪便排出。在尿液和血浆中，最初的代谢物是去甲酰头孢噻呋。放射性代谢物的高效液相色谱分析结果与大鼠研究的结果相似。产生了一系列代谢物，主要代谢物（占尿液代谢物总量的87%）是去甲酰头孢噻呋乙酰胺结合物。在尿液中没有观察到母体化合物。

A study of im administration of (14)C-ceftiofur in a bull revealed that 55% of the administered dose was excreted in the urine and approximately 30% in the GI tract and feces. The initial metabolite in both urine and plasma was desfuroylceftiofur. HPLC analysis of radioactive metabolites was similar to the results found in the rat studies. A number of metabolites were produced, the major metabolite (87% of total urinary metabolites) being desfuroylceftiofur acetamide conjugates. No parent compound was observed in the urine.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  2
• 海关编码：
  2941905700
• 危险品运输编号：
  5kgs

制备方法与用途

头孢噻呋简介

头孢噻呋是美国在20世纪80年代开发的第三代兽医专用头孢菌素。该药物于1988年首次在美国上市，因其优良的抗菌活性和药动学特性，已被多个国家正式批准用于治疗肉牛、奶牛、马匹、猪和羊等动物的呼吸道疾病。头孢噻呋为类白色至淡黄色粉末，在水中不溶，在丙酮中微溶，在乙醇中几乎不溶。

抗菌活性

**头孢噻呋**具有广泛的抗菌谱，对革兰氏阳性菌、阴性菌及一些厌氧菌都表现出强烈的抗菌活性。Yancy R J等人的研究表明，除金黄色葡萄球菌外，头孢噻呋对其他病原菌的抗菌活性均优于氨卞青霉素。Salmon S A 等的研究表明，头孢噻呋及其主要代谢物去呋喃羰基头孢噻呋对革兰氏阴性菌的抗菌活性相同或相近。

头孢菌素类抗生素

头孢噻呋是一种动物专用的第三代头孢菌素类抗生素。它具有广泛的抗菌谱和强大的抗菌活性，尤其对革兰阳性菌、革兰阴性菌及厌氧菌均表现出良好的效果。尽管对革兰阳性菌的作用与第一代头孢菌素相近或较弱，但它对大肠杆菌、伤寒沙门氏菌、多杀性和溶血性巴氏杆菌、链球菌等革兰阴性菌具有强大的抗菌活性。

该药物适用于治疗由各种敏感细菌引起的呼吸道和泌尿道感染。尤其对于防治鸡苗早期死亡（如由大肠杆菌、沙门氏杆菌、绿脓杆菌及葡萄球菌引起），1日龄仔猪的大肠杆菌性黄痢，以及剪脐带、打耳号、剪齿、剪尾等手术后的伤口感染等具有显著效果。头孢噻呋不适用于奶牛和奶羊乳腺炎的治疗。

头孢噻呋的特点是肌注吸收完全且消除半衰期长。注射用品种如头孢噻肟、头孢曲松对革兰阳性菌的作用不及第一代头孢菌素，但对肺炎链球菌（包括耐青霉素菌株）、化脓性链球菌及其他链球菌属有良好抗菌作用；对大肠埃希菌、肺炎克雷伯菌、奇异变形杆菌等革兰阴性杆菌有强大抗菌作用；对流感嗜血杆菌、脑膜炎奈瑟氏菌、淋病奈瑟氏菌及卡他莫拉菌的作用强，而对沙雷菌属、肠杆菌属、不动杆菌属及假单胞菌属的药物敏感性则差异较大。具有抗假单胞菌作用的品种如头孢他啶、头孢哌酮、头孢匹胺对革兰阳性球菌作用较差，但对革兰阴性杆菌的作用与其他第三代头孢类抗生素相似，且对铜绿假单胞菌有高度抗菌活性。

注意事项

1. 对头孢菌素过敏的动物禁用；青霉素过敏的动物慎用。
2. 马在应激条件下使用本品可能引起急性腹泻，并可能导致死亡。一旦发生，立即停药并采取相应治疗措施。
3. 肾功能不全的动物需调整剂量。
4. 注射用头孢噻呋钠临用前以注射用水溶解（每毫升含50毫克），冷藏保存可保持效用7天，在15-30℃室温中则保持12小时。使用前充分摇匀，不宜冷冻，首次使用后需在14天内用完。
5. 休药期：注射用头孢噻呋钠牛3天，猪2天；盐酸头孢噻呋混悬液牛2天。

用途

• 动物专用抗生素：用于治疗革兰阳性菌、阴性菌及霉形体感染等
• 兽药（原粉）

文献信息

• US20140274999A1
  申请人：——

  公开号：US20140274999A1

  公开（公告）日：2014-09-18