(4R,5S,6S,7R,9R,11E,13Z,15R,16S)-6-[(2R,3R,4S,5S,6R)-4-(Dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3S,5R)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-1-oxacyclohexadeca-11,13-diene-2,10-dione | 108050-54-0

• 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 - 有机氧化合物
• 英文名称: (4R,5S,6S,7R,9R,11E,13Z,15R,16S)-6-[(2R,3R,4S,5S,6R)-4-(Dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3S,5R)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-1-oxacyclohexadeca-11,13-diene-2,10-dione
• 英文别名: (4R,5S,6S,9R,11E,13E,15R,16R)-6-[(2R,3R,4S,5S,6R)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3R,5S)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-1-oxacyclohexadeca-11,13-diene-2,10-dione
• CAS: 108050-54-0
• 化学式: C₄₆H₈₀N₂O₁₃
• 分子量: 869.1
• InChiKey: JTSDBFGMPLKDCD-UYPDHHONSA-N

物化性质

• 熔点：
  >97°C (dec.)
• 比旋光度：
  D23 +12.75° (c = 0.010004 in CHCl3, 5 cm)
• 沸点：
  926.6±65.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 溶解度：
  丙酮（微溶）、DMSO（微溶）、甲醇（微溶）
• 蒸汽压力：
  4.6X10-32 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation = +12.75 °For D (sodium) line at 23 °C (c = 0.010004 in CHCl3, 5 cm)
• 解离常数：
  pKa = 8.18 (tertiary amine)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  61
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  186
• 氢给体数：
  4
• 氢受体数：
  15

ADMET

代谢

Beulah杂交羔羊单次皮下注射20 mg/kg bw/天的(14)C-替米考星。肝脏、肾脏和尿液中主要的放射性成分是母药，以及较少的T1和T2，还有少量的其他未识别物质。

Beulah cross lambs were administered a single subcutaneous dose of 20 mg/kg bw per day (14)C-tilmicosin. The major radioactive component in the liver, kidneys and urine was the parent drug, together with lesser amounts of T1 and T2, and minor amounts of other unidentified substances.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Fischer-344大鼠（10只雄性和10只雌性）每天口服50毫克/千克体重的(14)C-蒂尔米科辛，持续5天。对粪便中硫酸盐代谢物的粪便放射性进行分析，发现了与猪粪便中相似的化合物，但没有进行量化。

Fischer-344 rats (10 males and 10 females) were given gavage doses of 50 mg/kg bw per day (14)C-tilmicosin for 5 days. An analysis of fecal radioactivity for the presence of the sulfate metabolite that was found in the feces of pigs revealed the presence of a similar compound, but quantification was not undertaken.

来源:Hazardous Substances Data Bank (HSDB)

代谢

使用(14)C标记的地麦考星，在15只雄性和15只雌性Fischer-344大鼠中口服给药。剂量为每天20毫克/千克体重，持续3天。在肝脏中，放射性标记对应于地麦考星及其去甲基衍生物T1（在麦考糖环上去甲基化）。尿液中检出的单一放射性物质为未改变的地麦考星，而在粪便中，主要的放射性峰是母化合物，其次是去甲基地麦考星和一个高分子量化合物，该化合物已知作为给药物质中的杂质存在，T2（由两个大环内酯环和一个哌啶环组成）。

Tilmicosin, labelled with (14)C in both the desmycosin macrolide ring and the piperidine ring, was given orally to 15 male and 15 female Fischer-344 rats. The dosage was 20 mg/kg bw per day for 3 days. In the liver, radiolabel corresponded to tilmicosin and a desmethyl derivative, T1 (demethylated in the mycaminose ring). The single radioactive substance identified in urine was unchanged tilmicosin, while in feces the major peak was parent compound with lesser amounts of desmethyl tilmicosin and a high molecular weight compound known to be present as an impurity in the administered substance, T2 (consisting of two macrolide rings and one piperidine ring).

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给注射了(14)C-替米考星的结果概述中，报道称处理过的老鼠肝脏中的放射性活性轮廓与粪便中的相似。在使用高度纯化的替米考样品处理的动物中，代谢物T2在肝脏中未被检测到，这表明其存在是作为药物物质组成部分直接给药的结果。肾脏中的放射性活性基本上以未改变的替米考星形式存在。

In a summary of results obtained in cattle injected with (14)C-tilmicosin, it was reported that the radioactivity profile in the liver of treated rats was similar to that in the feces. In animals treated with a highly purified sample of tilmicosin, metabolite T2 was not detected in the liver, suggesting that its presence was a result of direct administration as a component of the drug substance. Radioactivity in the kidneys was essentially in the form of unchanged tilmicosin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

猪被喂食了含有放射性碳-14标记的泰妙菌素的食物，每天的剂量为400毫克，持续5天。在肝脏和肾脏中，大约60到70%的放射性标记以母药的形式存在，同时还存在少量的一级代谢物T1。同样，在尿液和粪便中，泰妙菌素的含量很高，而T1的含量很低。还检测到了另一种代谢物，它构成了粪便中14%和尿液中25%的放射性，这与大环内酯环中一个双键的还原然后硫酸化一致。

Pigs were fed diets containing (14)C-tilmicosin, which resulted in daily doses of 400 mg, for 5 days. Of the radiolabel in liver and kidney, approximately 60 to 70% was in the form of the parent drug and there were small amounts of T1. Similarly in urine and faeces, there were high levels of tilmicosin and low levels of T1. A further metabolite was detected that comprised 14% of faecal and 25% of urinary radioactivity and that was consistent with reduction of one double bond in the macrolide ring followed by sulfation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用卡马西平、环孢素、地高辛、己巴比妥、苯妥英或丙戊酸与大环内酯类抗生素，已与这些药物的血药浓度升高有关；建议监测同时给药的药物的血药浓度，以避免中毒。/大环内酯类抗生素/

Concurrent use /of carbamazepine, cyclosporine, digoxin, hexobarbital, phenytoin or valproic acid/ with macrolide antibiotics has been associated with increased serum concentration of these medications; monitoring of serum concentrations of medications administered concurrently is recommended to avoid toxicity. /Macrolide antibiotics/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

黄嘌呤类药物（除二羟丙茶碱外）与macrolides（大环内酯类抗生素）同时使用可能会减少黄嘌呤类药物的肝清除率，导致血清中药物浓度升高和/或毒性增加；在与大环内酯类抗生素治疗期间和治疗后，可能需要调整黄嘌呤类药物的剂量。

Concurrent use of the xanthines (except dyphylline) with macrolides may decrease hepatic clearance of xanthines, resulting in increased serum concentrations and/or toxicity; dosage adjustment of the xanthines may be necessary during and after therapy with macrolides. /Macrolide antibiotics/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用咪达唑仑或三唑仑与 macrolide 类抗生素可能会降低这些药物的清除率，增加咪达唑仑或三唑仑的药理作用。/Macrolide 类抗生素/

Concurrent use /of midazolam or triazolam/ with macrolide antibiotics may decrease the clearance of these medications, increasing the pharmacologic effect of midazolam or triazolam. /Macrolide antibiotics/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与 macrolide 抗生素同时使用与增加抗凝血作用有关；在接受抗凝药物和 macrolides 同时治疗的患者中应仔细监测凝血酶原时间。/Macrolide 抗生素/

Concurrent administration with macrolide antibiotics has been associated with increased anticoagulant effects; prothrombin time should be monitored carefully in patients receiving anticoagulants and macrolides concurrently. /Macrolide antibiotics/

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，进行辅助通气。通过非重复呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预防癫痫发作，并在必要时进行治疗……。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，如果患者能够吞咽、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)

吸收、分配和排泄

猪在饮食中接受了154毫克或400毫克（14）C-蒂尔米科辛的剂量，这是在连续5天给予相似剂量后的情况。放射性物质的恢复在尿液中为4%到6%，在粪便中为62%到75%。胆汁中检测到放射性物质，但未进行量化。

Pigs were given a dose of 154 or 400 mg (14)C-tilmicosin in the diet following a similar dose given for 5 days. The recovery of radioactivity was 4 to 6% in urine and 62 to 75% in feces. Radioactivity was detected in the bile but was not quantified.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

猪在一天内通过饲料摄入了110毫克（14）C-蒂尔米科辛。放射性物质的回收率在尿液中为15%，在粪便中为80%。

Pigs were administered a dose of 110 mg (14)C-tilmicosin in the diet over the course of one day. The recovery of radioactivity was 15% in the urine and 80% in the feces.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

替米考星通过皮下注射给药。注射后吸收迅速...

Tilmicosin is administered SC. Absorption after injection is rapid ... .

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Beulah杂交羔羊单次皮下注射20 mg/kg bw/天的(14)C-替米考星。肝脏、肾脏和尿液中主要的放射性成分是母药，以及较少的T1和T2，还有少量的其他未识别物质。

Beulah cross lambs were administered a single subcutaneous dose of 20 mg/kg bw per day (14)C-tilmicosin. The major radioactive component in the liver, kidneys and urine was the parent drug, together with lesser amounts of T1 and T2, and minor amounts of other unidentified substances.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 海关编码：
  29419090

制备方法与用途

畜禽专用抗生素——替米考星

替米考星 是一种较新的由泰乐菌素半合成的大环内酯类畜禽专用抗生素，化学名称为 4A-O-脱（2,6-二脱氧-3-C-甲基-L-核糖-吡喃己基）-20-脱氧-20-(3,5-二甲基-1-哌啶基)-[20(顺式:反式)]泰乐菌素，分子式为 C₄₆H₈₀N₂O₁₃，分子量 869.15。

替米考星的抗菌谱与泰乐菌素相似，在抗出血败血性巴斯德氏菌和溶血性巴斯德氏菌方面有增强作用。20世纪80年代开发成功，最初使用 EL-870 作为代号。常用的商品名有 Pulmotil© 和 Micotil©，制剂包括替米考星可溶性粉、预混剂（20%）、注射液。1990年在多数欧洲国家获得批准，1992年在美国获得批准，并收录于美国药典。中国国内也已经有一些企业获得了生产许可。

由于其特殊的抗菌活性和药动学特征，该药已被批准用于牛、山羊、绵羊、奶牛、猪、鸡等动物感染性疾病的防治。尤其适用于畜禽呼吸道疾病，如家畜放线杆菌、巴氏杆菌及支原体引起的感染。

体内研究

皮下注射后，替米考星从血清和乳液中消除较慢，半衰期（t₁/₂βS）分别为9.3小时和41.4小时。表观分布容积大于1升/千克。皮下注射10毫克/千克后的6.39小时内，血浆中替米考星浓度峰值为1.56微克/毫升。替米考星广泛地分泌到乳汁中，最大浓度可达11.6微克/毫升，乳汁AUC与血清AUC的比值约为12:1。单次皮下给药11天后，替米考星在乳汁中仍可检测。

配伍禁忌

• 与氟喹诺酮类药物联用时，两药药效可能部分抵消，甚至增加副作用。
• 与青霉素类药物呈拮抗作用，不宜联用。
• 替米考星可使头孢菌素类药物的快速杀菌效能受到明显抑制。
• 肾上腺素与替米考星合用可能导致猪死亡。

安全性

该药较为安全，无致癌、致畸或胚胎毒性，但可能产生心脏和肾脏毒性。有报道奶牛静注替米考星后出现急性心脏毒性，表现为共济失调、心动过速等临床症状，但30分钟内可恢复正常；注射部位可能出现肿胀。

也有替米考星应用于犬时引发上述心血管反应的报道。猪肌注5%替米考星注射液时，10毫克/千克体重剂量下出现呼吸急促、呕吐和惊厥等中毒症状；15毫克/千克体重的高剂量可导致危急病例死亡，20毫克/千克体重剂量在15分钟内致死率可达80%。这些不良反应多因使用剂量过大或给药方式不当所致。

替米考星主要经消化道排泄，用量少、用药次数少，药物毒副作用一般不明显，动物可完全耐受。

化学性质

• 白色或白色粉末。
• 湿度：≤5.0%。
• 易溶于甲醇和乙腈，在乙醇和丙二醇中溶解，在水中不溶。

用途

替米考星是由泰乐菌素的一种水解产物半合成的畜禽专用抗生素，与泰乐菌素、泰万菌素同属大环内酯类，主要用于治疗胸膜肺炎、放线杆菌及支原体引起的感染。